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1.  Microbiota-dependent sequelae of acute infection compromise tissue-specific immunity 
Cell  2015;163(2):354-366.
Summary
Infections have been proposed as initiating factors for inflammatory disorders, however, identifying associations between defined infectious agents and the initiation of chronic disease has remained elusive. Here, we report that a single acute infection can have dramatic and long-term consequences for tissue-specific immunity. Following clearance of Yersinia pseudotuberculosis, sustained inflammation and associated lymphatic leakage in the mesenteric adipose tissue deviates migratory dendritic cells to the adipose compartment, thereby preventing their accumulation in the mesenteric lymph node. As a consequence, canonical mucosal immune functions, including tolerance and protective immunity, are persistently compromised. Post-resolution of infection, signals derived from the microbiota maintain inflammatory mesentery remodeling and consequently, transient ablation of the microbiota restores mucosal immunity. Our results indicate that persistent disruption of communication between tissues and the immune system following clearance of an acute infection represents an inflection point beyond which tissue homeostasis and immunity is compromised for the long-term.
Graphical abstract
Long-term consequences of Yersinia pseudotuberculosis infection. At steady-state, migratory DCs acquire antigen in the GI tract and traffic to the mesenteric lymph nodes (MLN) via lymphatic vessels. Upon arrival in the MLN, migratory DCs induce the differentiation of Th17 and pTreg in the MLN. Following infection with Yersinia, lymphatics become leaky, leading to the shunting of migratory DCs and other immune cells to the mesenteric adipose tissue (MAT). The immune tone of the MAT switches from Type 2 to Type 1, with an increase in inflammatory cells. Sustained damage to the MLN and MAT is not associated with chronic YP infection. On the other hand, the microbiota is required for the maintenance of this response likely due to lymphatic leakage and subsequent increased exposure of the MAT to microbes/microbial ligands. MAT inflammation, lymphatic damage and deviation of DCs from their physiological path chronically disable the induction of mucosal immunity.
doi:10.1016/j.cell.2015.08.030
PMCID: PMC4826740  PMID: 26451485
2.  Tuning of Antigen Sensitivity by TCRT Cell Receptor-Dependent Negative Feedback Controls T Cell Effector Function in Inflamed Tissues 
Immunity  2014;40(2):235-247.
Activated T cells must mediate effector responses sufficient to clear pathogens while avoiding excessive tissue damage. Here we have combined dynamic intravital microscopy with ex vivo assessments of T cell cytokine responses to generate a detailed spatiotemporal picture of CD4+ T cell effector regulation in the skin. In response to antigen, effector T cells arrested transiently on antigen presenting cells, briefly producing cytokine and then resuming migration. Antigen recognition led to PD-1 upregulation of the programmed death-1 (PD-1) glycoprotein by T cells and blocking its canonical ligand, programmed death-ligand 1 (PD-L1), lengthened the duration of migration arrest and cytokine production, showing that PD-1 interaction with PD-L1 is a major negative feedback regulator of antigen responsiveness. We speculate that the immune system employs a mechanism involving T cell recruitment, transient activation, and rapid desensitization, allowing the T cell response to rapidly adjust to changes in antigen presentation and minimize collateral injury to the host.
doi:10.1016/j.immuni.2013.11.017
PMCID: PMC4792276  PMID: 24440150
PD-1; effector T cells; intravital imaging; cytokine production; immune regulation
3.  Healing the NIH-funded Biomedical Research Enterprise 
Cell  2015;161(7):1485-1491.
Summary
Many feel the RO1 grant system supporting biomedical research in the U.S. is broken, discouraging entry of young investigators into the system and inadequately supporting more established investigators. Here I argue for a ‘person not project’-based scheme that would permit creative, unfettered research by new investigators, better tie ongoing research contributions to continued funding, and help match the number of investigators seeking support with available funds.
doi:10.1016/j.cell.2015.05.052
PMCID: PMC4495897  PMID: 26091028
4.  Thymic Positive Selection and the Mature T Cell Repertoire for Antigen Revisited 
Immunity  2014;41(2):181-190.
To support effective host defense, the T cell repertoire must balance breadth of recognition with sensitivity for antigen. The concept that T lymphocytes are positively selected in the thymus is established, but this achieves such a repertoire has not been resolved. Here we suggest that it is direct linkage between self and foreign antigen recognition that produces the necessary blend of T cell receptor (TCR) diversity and specificity in the mature peripheral repertoire, enabling responses to a broad universe of unpredictable antigens while maintaining an adequate number of highly sensitive T cells in a population of limited size. Our analysis also helps to explain how diversity and frequency of antigen-reactive cells in a T cell repertoire are adjusted in animals of vastly different size scale to enable effective anti-pathogen responses and suggest a possible binary architecture in the TCR repertoire that is divided between germline-related optimal binding and diverse recognition.
doi:10.1016/j.immuni.2014.07.007
PMCID: PMC4152861  PMID: 25148022
5.  T Cell Receptor-dependent Signal Intensity Dominantly Controls CD4+ T Cell Polarization In Vivo 
Immunity  2014;41(1):63-74.
Summary
Polarization of effector CD4+ T cells can be influenced by both antigen-specific signals and by pathogen- or adjuvant-induced cytokines, with current models attributing a dominant role to the latter. Here we have examined the relationship between these factors in shaping cell-mediated immunity using intravital imaging of CD4+ T cell interactions with dendritic cells (DCs) exposed to polarizing adjuvants. These studies revealed a close correspondence between strength of T cell receptor (TCR)-dependent signaling and T helper-1 (Th1) vs. Th2 cell fate, with antigen concentration dominating over adjuvant in controlling T cell polarity. Consistent with this finding, at a fixed antigen concentration, adjuvants inducing Th1 cells operated by affecting DC costimulation that amplified TCR signaling. TCR signal strength controlled downstream cytokine receptor expression, linking the two components in a hierarchical fashion. These data reveal how quantitative integration of antigen display and costimulation regulates downstream checkpoints responsible for cytokine-mediated control of effector differentiation.
doi:10.1016/j.immuni.2014.06.003
PMCID: PMC4114069  PMID: 24981853
6.  Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes 
Nature medicine  2014;20(12):1458-1463.
Antibodies are critical for defence against a variety of microbes but may also be pathogenic in some autoimmune diseases. Many effector functions of antibody are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs). DCs are important antigen presenting cells and play a central role in inducing antigen-specific tolerance or immunity1,2. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via lymphatics to present antigen to T cells. In this study we demonstrate that FcγR engagement by IgG immune complexes (IC) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated murine and human DCs showed enhanced directional migration in a CCL19 gradient and increased CCR7 expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilisation. We confirmed that dermal DC migration to lymph nodes was CCR7-dependent and increased in the absence of the inhibitory receptor, FcγRIIb. These observations have relevance to autoimmunity, because autoantibody-containing serum from mice and humans with SLE also increased dermal DC migration to lymph nodes in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localisation of autoantigen-bearing DCs.
doi:10.1038/nm.3709
PMCID: PMC4283039  PMID: 25384086
7.  NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ–IL-27 axis 
The Journal of Experimental Medicine  2015;212(10):1739-1752.
DCs recruit NK cells to the draining lymph node where they interact with DC creating a positive feedback loop of IL-27 and IFNγ production, which is ultimately limited by IL-10. This innate NK-DC axis controls the development of the adaptive response and dampens induction of autoimmunity.
IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ−/− mice repleted with IFN-γ+/+ NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity. After immunization, DCs recruited IFN-γ-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC–dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10–producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits tissue-specific autoimmunity through an innate IFN-γ–IL-27 axis.
doi:10.1084/jem.20141678
PMCID: PMC4577839  PMID: 26347474
9.  ANTIGEN- AND CYTOKINE-DRIVEN ACCUMULATION OF REGULATORY T CELLS IN VISCERAL ADIPOSE TISSUE OF LEAN MICE 
Cell metabolism  2015;21(4):543-557.
SUMMARY
A unique population of Foxp3+CD4+ regulatory T (Treg) cells, with a distinct transcriptome and antigen-receptor repertoire, resides in visceral adipose tissue (VAT) of lean individuals. These cells regulate local inflammation and both local and systemic metabolic indices. Here we focus on expansion of the VAT Treg compartment in aging lean mice – assessing these cells’ phenotypic conversion from conventional CD4+ T cells, influx from lymphoid organs, and local population dynamics. Our findings establish that the VAT Treg compartment is seeded from thymocytes generated during the first weeks of life, and expands beyond 10 weeks of age due to indolent proliferation, of certain clones in particular, coupled with enhanced survival. Accumulation of VAT Tregs depends on antigen(s) presented by MHC class-II molecules and soluble mediators, notably interleukin(IL)-33. Addressing such factors therapeutically promises novel approaches for harnessing Tregs to stem the growing epidemic of obesity and consequent metabolic abnormalities.
doi:10.1016/j.cmet.2015.03.005
PMCID: PMC4747251  PMID: 25863247
10.  Continuous volumetric imaging via an optical phase-locked ultrasound lens 
Nature methods  2015;12(8):759-762.
In vivo imaging at high spatiotemporal resolution holds the key to the fundamental understanding of complex biological systems. Integrating an optical phase-locked ultrasound lens into a conventional two-photon fluorescence microscope, we achieved microsecond scale axial scanning, which enabled high-speed volumetric imaging. We applied this system to multicolor volumetric imaging of fast processes, including calcium dynamics in the cerebral cortex of behaving mice, and transient morphology changes and trafficking of immune cells.
doi:10.1038/nmeth.3476
PMCID: PMC4551496  PMID: 26167641
11.  Network representations of immune system complexity 
The mammalian immune system is a dynamic multi-scale system composed of a hierarchically organized set of molecular, cellular and organismal networks that act in concert to promote effective host defense. These networks range from those involving gene regulatory and protein-protein interactions underlying intracellular signaling pathways and single cell responses to increasingly complex networks of in vivo cellular interaction, positioning and migration that determine the overall immune response of an organism. Immunity is thus not the product of simple signaling events but rather non-linear behaviors arising from dynamic, feedback-regulated interactions among many components. One of the major goals of systems immunology is to quantitatively measure these complex multi-scale spatial and temporal interactions, permitting development of computational models that can be used to predict responses to perturbation. Recent technological advances permit collection of comprehensive datasets at multiple molecular and cellular levels while advances in network biology support representation of the relationships of components at each level as physical or functional interaction networks. The latter facilitate effective visualization of patterns and recognition of emergent properties arising from the many interactions of genes, molecules, and cells of the immune system. We illustrate the power of integrating ‘omics’ and network modeling approaches for unbiased reconstruction of signaling and transcriptional networks with a focus on applications involving the innate immune system. We further discuss future possibilities for reconstruction of increasingly complex cellular and organism-level networks and development of sophisticated computational tools for prediction of emergent immune behavior arising from the concerted action of these networks.
doi:10.1002/wsbm.1288
PMCID: PMC4339634  PMID: 25625853
12.  Immune homeostasis enforced by co-localized effector and regulatory T cells 
Nature  2015;528(7581):225-230.
Foxp3+ regulatory T cells (Tregs) play a critical role in preventing autoimmune disease by limiting the effector activity of conventional T cells that have escaped thymic negative selection or cell-autonomous peripheral inactivation1–3. However, despite the substantial information available about the molecular players mediating Treg functional interference with auto-aggressive effector responses4,5, the relevant cellular events in intact tissues remain largely unexplored and the issues of whether Tregs prevent activation of self-specific T cells or function primarily to limit damage from such cells have not been addressed6. Here we have employed multiplex, high-resolution, quantitative imaging to reveal that within most secondary lymphoid tissues, Tregs expressing phosphorylated STAT5 (pSTAT5) and high amounts of the suppressive molecules CD73 and CTLA-4 exist in discrete clusters with rare IL-2 producing effector T cells activated by self-antigens. This local IL-2 production induces the STAT5 phosphorylation in the Tregs and is part of a feedback circuit that augments the suppressive properties of the Tregs to limit further autoimmune responses. Inducible ablation of TCR expression by Tregs reduces their regulatory capacity and disrupts their localization in such clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells reach a state of activation and cytokine gene induction on a regular basis, with physically co-clustering, TCR-stimulated Tregs responding to this activation in a feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.
doi:10.1038/nature16169
PMCID: PMC4702500  PMID: 26605524
13.  The multiple faces of leukocyte interstitial migration 
Seminars in immunopathology  2014;36(2):227-251.
Spatiotemporal control of leukocyte dynamics within tissues is critical for successful innate and adaptive immune responses. Homeostatic trafficking and coordinated infiltration into and within sites of inflammation and infection rely on signaling in response to extracellular cues that in turn controls a variety of intracellular protein networks regulating leukocyte motility, migration, chemotaxis, positioning, and cell–cell interaction. In contrast to mesenchymal cells, leukocytes migrate in an amoeboid fashion by rapid cycles of actin polymerization and actomyosin contraction, and their migration in tissues is generally referred to as low adhesive and nonproteolytic. The interplay of actin network expansion, contraction, and adhesion shapes the exact mode of amoeboid migration, and in this review, we explore how leukocyte subsets potentially harness the same basic biomechanical mechanisms in a cell-type-specific manner. Most of our detailed understanding of these processes derives from in vitro migration studies in three-dimensional gels and confined spaces that mimic geometrical aspects of physiological tissues. We summarize these in vitro results and then critically compare them to data from intravital imaging of leukocyte interstitial migration in mouse tissues. We outline the technical challenges of obtaining conclusive mechanistic results from intravital studies, discuss leukocyte migration strategies in vivo, and present examples of mode switching during physiological interstitial migration. These findings are also placed in the context of leukocyte migration defects in primary immunodeficiencies. This overview of both in vitro and in vivo studies highlights recent progress in understanding the molecular and biophysical mechanisms that shape robust leukocyte migration responses in physiologically complex and heterogeneous environments.
doi:10.1007/s00281-014-0418-8
PMCID: PMC4118216  PMID: 24573488
Leukocyte; Interstitial migration; Plasticity; Cytoskeleton; Tissue architecture; Imaging
14.  A Systems Analysis Identifies a Feed-forward Inflammatory Circuit Leading to Lethal Influenza Infection 
Cell  2013;154(1):197-212.
Summary
For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium vs. dysregulated immunity remain unresolved. Here we take a top-down systems approach to this question. Multigene transcriptional signatures from infected lungs suggested that elevated activation of inflammatory signaling networks distinguished lethal from sublethal infections. Flow cytometry and gene expression analysis involving isolated cell subpopulations from infected lungs showed that neutrophil influx largely accounted for the predictive transcriptional signature. Automated imaging analysis together with these gene expression and flow data identified a chemokine-driven feed-forward circuit involving pro-inflammatory neutrophils potently driven by poorly contained lethal viruses. Consistent with these data, attenuation but not ablation of the neutrophil-driven response increased survival without changing viral spread. These findings establish the primacy of damaging innate inflammation in at least some forms of influenza-induced lethality and provide a roadmap for the systematic dissection of infection-associated pathology.
doi:10.1016/j.cell.2013.06.013
PMCID: PMC3763506  PMID: 23827683
15.  The Future of Immuno-imaging – Deeper, Bigger, More Precise, and Definitively More Colorful 
European journal of immunology  2013;43(6):1407-1412.
Immune cells are thoroughbreds, moving farther and faster and surveying more diverse tissue space than their non-hematopoietic brethren. Intravital 2-photon microscopy has provided insights into the movements and interactions of many immune cell types in diverse tissues, but much more information is needed to link such analyses of dynamic cell behavior to function. Here we describe additional methods whose application promises to extend our vision, allowing more complete, multiscale dissection of how immune cell positioning and movement are linked to system state, host defense, and disease.
doi:10.1002/eji.201243119
PMCID: PMC3748132  PMID: 23568494
2-photon; dynamic; imaging; in vivo; multicolor
16.  The adapter MAVS promotes NLRP3 mitochondrial localization and inflammasome activation 
Cell  2013;153(2):348-361.
Summary
NLRP3 is a key component of the macromolecular signaling complex called the inflammasome that promotes caspase 1-dependent production of IL-1β. The adapter ASC is necessary for NLRP3-dependent inflammasome function, but it is not known if ASC is a sufficient partner, and whether inflammasome formation occurs in the cytosol or in association with mitochondria is controversial. Here we show that the mitochondria-associated adapter molecule, MAVS, is required for optimal NLRP3 inflammasome activity. MAVS mediates recruitment of NLRP3 to mitochondria, promoting production of IL-1β and the pathophysiologic activity of the NLRP3 inflammasome in vivo. Our data support a more complex model of NLRP3 inflammasome activation than previously appreciated, with at least two adapters required for maximal function. Since MAVS is a mitochondria-associated molecule previously considered to be uniquely involved in type 1 interferon production, these findings also reveal unexpected polygamous involvement of PYD/CARD domain-containing adapters in innate immune signaling events.
doi:10.1016/j.cell.2013.02.054
PMCID: PMC3632354  PMID: 23582325
17.  Peripheral pre-positioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node 
Immunity  2013;38(3):502-513.
Summary
After an infection, the immune system generates long-lived memory lymphocytes whose increased frequency and altered state of differentiation enhance host defense against re-infection. Recently, the spatial distribution of memory cells was found to contribute to their protective function. Effector memory CD8+ T cells reside in peripheral tissue sites of initial pathogen encounter, in apparent anticipation of re-infection. Here we show that within lymph nodes (LN), memory CD8+ T cells were concentrated near peripheral entry portals of lymph-borne pathogens, promoting rapid engagement of infected sentinel macrophages. A feed-forward CXCL9-dependent circuit provided additional chemotactic cues that further increase local memory cell density. Memory CD8+ T cells also produced effector responses to local cytokine triggers, but their dynamic behavior differed from that seen following antigen recognition. These data reveal the distinct localization and dynamic behavior of naive vs. memory T cells within LN and how these differences contribute to host defense.
doi:10.1016/j.immuni.2012.11.012
PMCID: PMC3793246  PMID: 23352234
18.  T Cell Positive Selection Uses Self-Ligand Binding Strength to Optimize Repertoire Recognition of Foreign Antigens 
Immunity  2013;38(2):263-274.
SUMMARY
Developing T cells express diverse antigen receptors whose specificities are not pre-matched to the foreign antigens they eventually encounter. Past experiments have revealed that thymocytes must productively signal in response to self-antigens to mature and enter the peripheral T cell pool (positive selection), but how this process enhances effective mature T cell responses to foreign antigen is not fully understood. Here we have documented an unsuspected connection between thymic recognition events and foreign antigen-driven T cell responses. We find that the strength of self-reactivity is a clone-specific property unexpectedly directly related to the strength of T cell receptor (TCR) binding to presented foreign antigen. T cells with receptors showing stronger interaction with self dominate in responses to infections and accumulate in aging individuals, revealing that positive selection contributes to effective immunity by skewing the mature TCR repertoire towards highly effective recognition of pathogens that pose a danger to the host.
doi:10.1016/j.immuni.2012.09.011
PMCID: PMC3785078  PMID: 23290521
19.  A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread 
Cell  2012;150(6):1235-1248.
Summary
The lymphatic network that transports interstitial fluid and antigens to lymph nodes constitutes a conduit system that can be hijacked by invading pathogens to achieve systemic spread unless dissemination is blocked in the lymph node itself. Here we show that a network of diverse lymphoid cells (NK cells, γδ T cells, NKT cells, and innate-like CD8+ T cells) are spatially pre-positioned close to lymphatic sinus-lining sentinel macrophages where they can rapidly and efficiently receive inflammasome-generated IL-18 and additional cytokine signals from the pathogen-sensing phagocytes. This leads to rapid IFNγ secretion by the strategically positioned innate lymphocytes, fostering anti-microbial resistance in the macrophage population. Interference with this innate immune response loop allows systemic spread of lymph-borne bacteria. These findings extend our understanding of the functional significance of cellular positioning and local intercellular communication within lymph nodes, while emphasizing the role of these organs as highly active locations of innate host defense.
doi:10.1016/j.cell.2012.07.021
PMCID: PMC3514884  PMID: 22980983
20.  Histo-Cytometry: in situ multiplex cell phenotyping, quantification, and spatial analysis applied to dendritic cell subset micro-anatomy in lymph nodes 
Immunity  2012;37(2):364-376.
Summary
Flow cytometry allows highly quantitative analysis of complex dissociated populations at the cost of neglecting their tissue localization. In contrast, conventional microscopy methods provide spatial information, but visualization and quantification of cellular subsets defined by complex phenotypic marker combinations is challenging. Here we describe an analytical microscopy method, "Histo-Cytometry," for visualizing and quantifying phenotypically complex cell populations directly in tissue sections. This technology is based on multiplexed antibody staining, tiled high-resolution confocal microscopy, voxel gating, volumetric cell rendering, and quantitative analysis. We have tested this technology on various innate and adaptive immune populations in murine lymph nodes (LN) and were able to identify complex cellular subsets and phenotypes, achieving quantitatively similar results to flow cytometry, while also gathering cellular positional information. Here, we employ Histo-Cytometry to describe the spatial segregation of resident and migratory dendritic cell subsets into specialized micro-anatomical domains, suggesting an unexpected LN demarcation into discrete functional compartments.
doi:10.1016/j.immuni.2012.07.011
PMCID: PMC3514885  PMID: 22863836
21.  Treg Selectively Control CD8+ T Cell Effector Pool Size via IL-2 Restriction 
Treg are key players in maintaining immunhomeostasis but have also been shown to regulate immune responses against infectious pathogens. Therefore Treg are a promising target for modulating immune responses to vaccines in order to improve their efficacy. Using a viral vector system, we found that Treg act on the developing immune response early after infection by reducing the extent of dendritic cell costimulatory molecule expression. Due to this change and the lower IL-2 production that results, a substantial fraction of CD8+ effector T cells lose CD25 expression several days after activation. Surprisingly, such Treg-dependent limitations in IL-2 signaling by antigen-activated CD8+ T cells prevent effector differentiation without interfering with memory cell formation. In this way Treg fine-tune the numbers of effector T cells generated, while preserving the capacity for a rapid recall response upon pathogen re-exposure. This selective effect of Treg on a subpopulation of CD8+ T cells indicates that while manipulation of the Treg compartment might not be optimal for prophylactic vaccinations, it can be potentially exploited to optimize vaccine efficacy for therapeutic interventions.
doi:10.4049/jimmunol.1101649
PMCID: PMC3169715  PMID: 21849683
22.  DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity 
The Journal of Experimental Medicine  2014;211(13):2549-2566.
Zhang et al. show that DOCK8-deficient T and NK cells develop cell and nuclear shape abnormalities that do not impair chemotaxis but contribute to a form of cell death they term cytothripsis. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells resulting in impaired immune response to skin infection.
DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin.
doi:10.1084/jem.20141307
PMCID: PMC4267229  PMID: 25422492
23.  The In Situ Dynamics of Dendritic Cell Interactions 
European Journal of Immunology  2010;40(8):2103-2106.
Dendritic cells (DCs) regulate T cell function by promoting either tolerance or activation, and in the latter case, by directing response quality. New imaging tools now permit direct visualization of the relevant DC-T cell interactions in vivo and have provided a new perspective on the dynamics of these crucial cellular contacts. Here we discuss the insights generated by these analyses and the controversies/unanswered questions that need to be addressed in future work.
doi:10.1002/eji.201040482
PMCID: PMC3393769  PMID: 20853494
24.  Global analyses of human immune variation reveal baseline predictors of post-vaccination responses 
Cell  2014;157(2):499-513.
A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of post-vaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time-points. Most of the parameters contributing to prediction delineated temporally-stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.
doi:10.1016/j.cell.2014.03.031
PMCID: PMC4139290  PMID: 24725414
25.  Intravital Imaging Reveals Limited Antigen Presentation and T Cell Effector Function in Mycobacterial Granulomas 
Immunity  2011;34(5):807-819.
Summary
Cell-mediated adaptive immunity is critical for host defense, but little is known about T cell behavior during delivery of effector function. Here we investigate relationships among antigen presentation, T cell motility, and local production of effector cytokines by CD4+ T cells within hepatic granulomas triggered by Bacille Calmette-Guérin or Mycobacterium tuberculosis. At steady-state, only small fractions of mycobacteria-specific T cells showed antigen-induced migration arrest within granulomas, resulting in low-level, polarized secretion of cytokines. However, exogenous antigen elicited rapid arrest and robust cytokine production by the vast majority of effector T cells. These findings suggest that limited antigen presentation and/or recognition within granulomas evoke a muted T cell response drawing on only a fraction of the host’s potential effector capacity. Our results provide new insights into the regulation of host protective functions, especially how antigen availability influences T cell dynamics and in turn, effector T cell function during chronic infection.
doi:10.1016/j.immuni.2011.03.022
PMCID: PMC3164316  PMID: 21596592

Results 1-25 (76)