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1.  The natural defense system and the normative self model 
F1000Research  2016;5:797.
Infectious agents are not the only agressors, and the immune system is not the sole defender of the organism. In an enlarged perspective, the ‘normative self model’ postulates that a ‘natural defense system’ protects man and other complex organisms against the environmental and internal hazards of life, including infections and cancers. It involves multiple error detection and correction mechanisms that confer robustness to the body at all levels of its organization. According to the model, the self relies on a set of physiological norms, and NONself (meaning : Non Obedient to the Norms of the self) is anything ‘off-norms’. The natural defense system comprises a set of ‘civil defenses’ (to which all cells in organs and tissues contribute), and a ‘professional army ‘, made of a smaller set of mobile cells. Mobile and non mobile cells differ in their tuning abilities. Tuning extends the recognition capabilities of NONself by the mobile cells, which increase their defensive function. To prevent them to drift, which would compromise self/NONself discrimination, the more plastic mobile cells need to periodically refer to the more stable non mobile cells to keep within physiological standards.
PMCID: PMC4890299  PMID: 27303629
systems biology; complexity; physiology; robustness; immune system; quality control; network; self non self discrimination
2.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
PMCID: PMC3221551  PMID: 21745417
3.  IL-1β, IL-6, and RANTES as Biomarkers of Chikungunya Severity 
PLoS ONE  2009;4(1):e4261.
Little is known about the immunopathogenesis of Chikungunya virus. Circulating levels of immune mediators and growth factors were analyzed from patients infected during the first Singaporean Chikungunya fever outbreak in early 2008 to establish biomarkers associated with infection and/or disease severity.
Methods and Findings
Adult patients with laboratory-confirmed Chikungunya fever infection, who were referred to the Communicable Disease Centre/Tan Tock Seng Hospital during the period from January to February 2008, were included in this retrospective study. Plasma fractions were analyzed using a multiplex-microbead immunoassay. Among the patients, the most common clinical features were fever (100%), arthralgia (90%), rash (50%) and conjunctivitis (40%). Profiles of 30 cytokines, chemokines, and growth factors were able to discriminate the clinical forms of Chikungunya from healthy controls, with patients classified as non-severe and severe disease. Levels of 8 plasma cytokines and 4 growth factors were significantly elevated. Statistical analysis showed that an increase in IL-1β, IL-6 and a decrease in RANTES were associated with disease severity.
This is the first comprehensive report on the production of cytokines, chemokines, and growth factors during acute Chikungunya virus infection. Using these biomarkers, we were able to distinguish between mild disease and more severe forms of Chikungunya fever, thus enabling the identification of patients with poor prognosis and monitoring of the disease.
PMCID: PMC2625438  PMID: 19156204
4.  Lineage relationships, homeostasis, and recall capacities of central– and effector–memory CD8 T cells in vivo 
The lineage relationships of central–memory T cells (TCM) cells and effector–memory T cells (TEM), as well as their homeostasis and recall capacities, are still controversial. We investigated these issues in a murine model using two complementary approaches: T cell receptor repertoire analysis and adoptive transfer experiments of purified H-Y–specific TCM and TEM populations. Repertoire studies showed that approximately two thirds of TCM and TEM clones derived from a common naive precursor, whereas the other third was distinct. Both approaches highlighted that TCM and TEM had drastically distinct behaviors in vivo, both in the absence of antigen or upon restimulation. TCM clones were stable in the absence of restimulation and mounted a potent and sustained recall response upon secondary challenge, giving rise to both TCM and TEM, although only a fraction of TCM generated TEM. In contrast, TEM persisted for only a short time in the absence of antigen and, although a fraction of them were able to express CD62L, they were unable to mount a proliferative response upon secondary challenge in this model.
PMCID: PMC2213051  PMID: 15710650
5.  Extrathymic T Cell Lymphopoiesis 
In the absence of thymopoiesis, T lymphocytes are nevertheless present, mainly in the gut epithelium. Ontogeny of the extrathymic pathway and the extent of its involvement in euthymic mice are controversial. These questions have been addressed by assessing the expression of recombinase activating gene (RAG) through the use of green fluorescent protein RAG2 transgenic mouse models. In athymic mice, T lymphopoiesis occurs mainly in the mesenteric lymph node and less in the Peyer's patches. Ontogenic steps of this lymphopoiesis resemble those of thymopoiesis, but with an apparent bias toward γδ T cell production and with a paucity of oligoclonal αβ T cells possibly resulting from a deficit in positive selection. Whether in athymic or euthymic mice, neither T intraepithelial lymphocytes (IEL) nor cryptopatch cells (reported to contain precursors of IEL) displayed fluorescence indicating recent RAG protein synthesis. Newly made T cells migrate from the mesenteric node into the thoracic duct lymph to reach the gut mucosa. In euthymic mice, this extrathymic pathway is totally repressed, except in conditions of severe lymphocytic depletion. Thus, in normal animals, all gut T IEL, including CD8αα+ cells, are of thymic origin, CD8αα+ TCRαβ+ IEL being the likely progeny of double negative NK1-1− thymocytes, which show polyclonal Vα and Vβ repertoires.
PMCID: PMC2193840  PMID: 12566417
T lymphocytes; extrathymic differentiation; gut intraepithelial lymphocytes; recombinase activating gene; mucosal immunity
6.  Most α/β T Cell Receptor Diversity Is Due to Terminal Deoxynucleotidyl Transferase 
The Journal of Experimental Medicine  2001;194(9):1385-1390.
The contribution of template-independent nucleotide addition to antigen receptor diversity is unknown. We therefore determined the size of the T cell receptor (TCR)α/β repertoire in mice bearing a null mutation on both alleles of the terminal deoxynucleotidyl transferase (Tdt) gene. We used a method based upon polymerase chain reaction amplification and exhaustive sequencing of various AV-AJ and BV-BJ combinations. In both wild-type and Tdt°/° mice, TCRAV diversity is one order of magnitude lower than the TCRBV diversity. In Tdt°/° animals, TCRBV chain diversity is reduced 10-fold compared with wild-type mice. In addition, in Tdt°/° mice, one BV chain can associate with three to four AV chains as in wild-type mice. The α/β repertoire size in Tdt°/° mice is estimated to be 105 distinct receptors, ∼5–10% of that calculated for wild-type mice. Thus, while Tdt activity is not involved in the combinatorial diversity resulting from α/β pairing, it contributes to at least 90% of TCRα/β diversity.
PMCID: PMC2195970  PMID: 11696602
T cell repertoire; T cell receptor; knockout mice; terminal deoxynucleotidyl transferase; CDR3
7.  Identical T Cell Clones Are Located within the Mouse Gut Epithelium and Lamina Propria and Circulate in the Thoracic Duct Lymph 
Murine gut intraepithelial (IEL) T cell receptor (TCR)-α/β1 lymphocytes bearing CD8α/β or CD8α/α coreceptors have been shown previously to express different oligoclonal TCR β chain repertoires in the same mouse, in agreement with other evidence indicating that these two populations belong to different ontogenic lineages, with only CD8α/β1 IELs being fully thymus dependent. CD8α/β1, but not CD8α/α1, T lymphocytes are also present in the lamina propria. Here, we show that CD8α/β+ lymphocytes from the lamina propria and the epithelium are both oligoclonal, and that they share the same TCR-β clonotypes in the same mouse, as is also the case for CD4+ T cells. Furthermore, identical T cell clones were detected among CD8α/β1 IELs and CD8α/β1 blasts circulating into the thoracic duct (TD) lymph of the same mouse, whereas TD small lymphocytes are polyclonal. These findings must be considered in light of previous observations showing that T blasts, but not small T lymphocytes, circulating in the TD lymph have the capacity of homing into the gut epithelium and lamina propria. These combined observations have interesting implications for our understanding of the recirculation of gut thymus-dependent lymphocytes and their precursors, and of the events leading up to the selection of their restricted TCR repertoire.
PMCID: PMC2195856  PMID: 10755885
gut lymphocyte; TCR-β repertoire; lymphocyte circulation; thoracic duct lymphocyte
8.  The Composition of a Primary T Cell Response Is Largely Determined by the Timing of Recruitment of Individual T Cell Clones  
The Journal of Experimental Medicine  1999;189(10):1591-1600.
Primary T cell responses rely on the recruitment and proliferation of antigen-specific T cell precursors. The extent of expansion of each individual T cell clone may depend on (a) its frequency before immunization, (b) its proliferative capacity, and (c) the time at which it first encounters its cognate antigen. In this report, we have analyzed the relative contribution of each of these parameters to the shaping of immune repertoires in the T cell response specific for the epitope 170-179 derived from HLA-Cw3 and presented by Kd. By means of hemisplenectomy, we compared immune and naive repertoires in the same animal and found that the frequency of all expanded T cell clones was extremely low before immunization. In particular, the most expanded clones did not derive from high-frequency precursors. In addition, recruited T cells were found to proliferate at the same rate, irrespective of their T cell antigen receptor sequence. Finally, we showed that only T cells that encounter the antigen at early time points account for a significant part of the specific response. Therefore, the contribution of a T cell clone to the immune response is mostly determined by the time of its entry into the immune repertoire, i.e., the time of first cell division after antigen encounter.
PMCID: PMC2193643  PMID: 10330438
clonal expansion; CD8 T cells; primary response; antigen-specific repertoire; major histocompatibility complex–peptide tetramers
9.  Implication of γδ T cells in the human immune response to cytomegalovirus 
Journal of Clinical Investigation  1999;103(10):1437-1449.
In normal individuals, γδ T cells account for less than 6% of total peripheral T lymphocytes and mainly express T-cell receptor (TCR) Vδ2-Vγ9 chains. We have previously observed a dramatic expansion of γδ T cells in the peripheral blood of renal allograft recipients only when they developed cytomegalovirus (CMV) infection. This increase was long lasting (more than 1 year), was associated with an activation of γδ T cells, and concerned only Vδ1 or Vδ3 T-cell subpopulations. Analysis of γδ TCR junctional diversity revealed that CMV infection in these patients was accompanied by (a) a marked restriction of CDR3 size distribution in Vδ3 and, to a lesser extent, in Vδ1 chains; and (b) a selective expansion of Vδ1 cells bearing recurrent junctional amino acid motifs. These features are highly suggestive of an in vivo antigen-driven selection of γδ T-cell subsets during the course of CMV infection. Furthermore, Vδ1 and Vδ3 T cells from CMV-infected kidney recipients were able to proliferate in vitro in the presence of free CMV or CMV-infected fibroblast lysates but not uninfected or other herpes virus–infected fibroblast lysates. This in vitro expansion was inhibited by anti-γδ TCR mAb’s. These findings suggest that a population of γδ T cells might play an important role in the immune response of immunosuppressed patients to CMV infection.
PMCID: PMC408467  PMID: 10330426
10.  Altered Expression of Tyrosine Kinases of the Src and Syk Families in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines 
Journal of Virology  1999;73(5):3709-3717.
During the late phase of adult T-cell leukemia/lymphoma, a severe lymphoproliferative disorder caused by human T-cell leukemia virus type 1 (HTLV-1), leukemic cells no longer produce interleukin-2. Several studies have reported the lack of the Src-like protein tyrosine kinase Lck and overexpression of Lyn and Fyn in these cells. In this report we demonstrate that, in addition to the downregulation of TCR, CD45, and Lck (which are key components of T-cell activation), HTLV-1-infected cell lines demonstrate a large increase of FynB, a Fyn isoform usually poorly expressed in T cells. Furthermore, similar to anergic T cells, Fyn is hyperactive in one of these HTLV-1-infected T-cell lines, probably as a consequence of Csk downregulation. A second family of two proteins, Zap-70 and Syk, relay the signal of T-cell activation. We demonstrate that in contrast to uninfected T cells, Zap-70 is absent in HTLV-1-infected T cells, whereas Syk is overexpressed. In searching for the mechanism responsible for FynB overexpression and Zap-70 downregulation, we have investigated the ability of the Tax and Rex proteins to modulate Zap-70 expression and the alternative splicing mechanism which gives rise to either FynB or FynT. By using Jurkat T cells stably transfected with the tax and rex genes or inducibly expressing the tax gene, we found that the expression of Rex was necessary to increase fynB expression, suggesting that Rex controls fyn gene splicing. Conversely, with the same Jurkat clones, we found that the expression of Tax but not Rex could downregulate Zap-70 expression. These results suggest that the effect of Tax and Rex must cooperate to deregulate the pathway of T-cell activation in HTLV-1-infected T cells.
PMCID: PMC104146  PMID: 10196263
11.  Conserved T Cell Receptor Repertoire in Primary and Memory CD8 T Cell Responses to an Acute Viral Infection  
Viral infections often induce potent CD8 T cell responses that play a key role in antiviral immunity. After viral clearance, the vast majority of the expanded CD8 T cells undergo apoptosis, leaving behind a stable number of memory cells. The relationship between the CD8 T cells that clear the acute viral infection and the long-lived CD8 memory pool remaining in the individual is not fully understood. To address this issue, we examined the T cell receptor (TCR) repertoire of virus-specific CD8 T cells in the mouse model of infection with lymphocytic choriomeningitis virus (LCMV) using three approaches: (a) in vivo quantitative TCR β chain V segment and complementarity determining region 3 (CDR3) length repertoire analysis by spectratyping (immunoscope); (b) identification of LCMV-specific CD8 T cells with MHC class I tetramers containing viral peptide and costaining with TCR Vβ–specific antibodies; and (c) functional TCR fingerprinting based on recognition of variant peptides. We compared the repertoire of CD8 T cells responding to acute primary and secondary LCMV infections, together with that of virus-specific memory T cells in immune mice. Our analysis showed that CD8 T cells from several Vβ families participated in the anti-LCMV response directed to the dominant cytotoxic T lymphocyte (CTL) epitope (NP118–126). However, the bulk (∼70%) of this CTL response was due to three privileged T cell populations systematically expanding during LCMV infection. Approximately 30% of the response consisted of Vβ10+ CD8 T cells with a β chain CDR3 length of nine amino acids, and 40% consisted of Vβ8.1+ (β CDR3 = eight amino acids) and Vβ8.2+ cells (β CDR3 = six amino acids). Finally, we showed that the TCR repertoire of the primary antiviral CD8 T cell response was similar both structurally and functionally to that of the memory pool and the secondary CD8 T cell effectors. These results suggest a stochastic selection of memory cells from the pool of CD8 T cells activated during primary infection.
PMCID: PMC2525546  PMID: 9653085
immunological memory; CD8 T cells; viral immunity; T cell receptor; lymphocytic choriomeningitis virus
12.  Quantitative Analysis of the T Cell Repertoire Selected by a Single Peptide–Major Histocompatibility Complex  
The Journal of Experimental Medicine  1998;187(11):1871-1883.
The positive selection of CD4+ T cells requires the expression of major histocompatibility complex (MHC) class II molecules in the thymus, but the role of self-peptides complexed to class II molecules is still a matter of debate. Recently, it was observed that transgenic mice expressing a single peptide–MHC class II complex positively select significant numbers of diverse CD4+ T cells in the thymus. However, the number of selected T cell specificities has not been evaluated so far. Here, we have sequenced 700 junctional complementarity determining regions 3 (CDR3) from T cell receptors (TCRs) carrying Vβ11-Jβ1.1 or Vβ12-Jβ1.1 rearrangements. We found that a single peptide–MHC class II complex positively selects at least 105 different Vβ rearrangements. Our data yield a first evaluation of the size of the T cell repertoire. In addition, they provide evidence that the single Eα52-68–I-Ab complex skews the amino acid frequency in the TCR CDR3 loop of positively selected T cells. A detailed analysis of CDR3 sequences indicates that a fraction of the β chain repertoire bears the imprint of the selecting self-peptide.
PMCID: PMC2212317  PMID: 9607927
thymus; major histocompatibility complex; T cell receptors; repertoire development; transgenic/knockout
13.  A cDNA clone containing the entire coding sequence of a mouse H-2Kd histocompatibility antigen 
Nucleic Acids Research  1983;11(5):1567-1577.
We have isolated a cDNA clone carrying a 1560 bp long insert which contains the entire coding and 3′ untranslated regions of an H-2Kd mouse histocompatibility antigen. Its sequence and overal features are described. They point to the existence of unique properties of DNA sequences associated with the H-2Kd antigen.
PMCID: PMC325816  PMID: 6298749

Results 1-13 (13)