The evidence briefly summarized herein provides multiple scenarios where MCs can be intimately linked to T cell biology and function. A common theme emerges whereby MC and T cell communication is regulatory in nature but not indispensable to carry out many of the effector functions of either cell type. There is evidence that:
- MCs can present antigen to T cells. However, there are many types of antigen presenting cells and MCs do not appear to be professional antigen presenting cells like dendritic cells.
- MCs can stimulate the proliferation of T effector cells. MCs appear to counteract the suppressive role of Tregs leading to increased T effector proliferation and function and this requires the OX40-OX40L axis and IL-6 production.
- MCs can interact with Tregs via the OX40L-OX40 interactions, respectively. OX40 engagement suppresses Treg function (appears to shift some Tregs to IL-17 production).
- Tregs can suppress some MC effector functions (particularly degranulation). OX40-OX40L interactions promotes cAMP in mast cells dampening calcium mobilization and thus degranulation.
- Under certain circumstances, MCs may serve as the effector arm of Treg-mediated suppression and MCs may also serve to break tolerance upon their activation.
Having been discovered more than a century ago, it seems rather remarkable that the regulatory role for MCs remained elusive for so long. However, until recently, there has been a lack of information on the physiological role of MCs beyond allergy. Naturally, the need for an understanding of the in vivo role of MCs compromises the understanding of MC and T cell interactions in health and disease and, importantly, the ability to devise therapeutic strategies by modulation of such interactions.
There are several reasons, both conceptual and technical, for the relative paucity of in vivo
studies. Perhaps the most critical problem is the lack of an appropriate mouse model, in which the sole problem is the absence of MC. Currently, the gold standard for demonstration of in vivo
MC function are lines arising from a spontaneous mutation (W/Wv
] or chromosomal inversion (Wsh/Wsh
] of the Kit gene. These MC-deficient mice have multiple defects including immunological and hematological abnormalities. For example, Wsh/Wsh
mice may develop splenomegaly with expanded myeloid and megakaryocyte populations and aberrant bone marrow and when repopulated with MCs not all tissues repopulate like wild type mice [76
]. These abnormalities can potentially exert effects on MC and T cell communication and/or function. In order to draw conclusions about the role of MCs, one is required to compare wild type mice with both MC reconstituted and non-MC reconstituted mice. Ideally, since W/Wv
differ in their abnormalities, studies should include both strains of mice to ascertain that the reconstituted effect is indeed mediated by MCs. Apart from being technically lengthy, cumbersome and expensive, this type of protocol possesses several inherent biological drawbacks. First, reconstitution is invariably done with bone marrow derived cultured MC. These cells are differentiated in vitro
, they are immature and they do not accurately recapitulate the different MC phenotypes found in vivo
]. Heterogeneity of MCs in tissues is a hallmark of their in vivo
localization and while two major types of MCs have been described, connective tissue and mucosal MCs, its is likely that MC heterogeneity is widely varied and depends on the specific microenvironment in which they reside [16
]. A second major disadvantage of MC reconstitution models is the clear difference in the numbers and tissue distribution of MCs when comparing MC-reconstituted Kit-deficient mice to wild type mice. For reasons that are not entirely clear, intravenous injection of MCs results in a massive engraftment in the spleen but not in the skin and other sites [78
]. To some extent this can be overcome by intradermal reconstitution of MCs, however, it is not known whether the local skin reconstitution would alter MC interactions and/or trafficking that may be needed to manifest their regulatory role, such as their presence in lymphoid secondary tissues. We anticipate that future breakthroughs in the understanding of MC function in health and disease will require better mouse models that enable their specific depletion and genetic manipulation.
As alluded to above, the functional hierarchy between MCs and T cells differs and this needs to be considered in the investigation of their interactions. T cells, both regulatory and effector subsets are critical for immunological homeostasis [80
]. Global or specific alterations may result in immunodeficiencies and even fatal phenotypes. The same is not true for MCs, whose deficiency is not associated with considerable spontaneous manifestations of disease in mice. Moreover, to the best of our knowledge, there is no described human disease of MC deficiency. This can be viewed as the MC being vital and thus MC-deficiencies are not viable, however, multiple lines of evidence argue against this notion. Both c-Kit and STAT5 [83
] -deficient mice, which are MC-deficient, are viable. Suppression of MC function with pharmacological agents in humans or in mice does not result in high susceptibility to infectious disease nor affect the viability of the MC [84
]. Taken together, we conclude that the MC fine tunes the immunological responses. Long term, chronic, immunological models in mice where MCs are specifically depleted will probably yield considerably more insight on the role of the MC in vivo
and its impact on the T cell compartment.
In summary, the body of data on MC signaling and function, which has accumulated thus far, offers a number of mechanisms for potential MC communication with T-cell. Several of these cooperations have been demonstrated both in vitro
and in vivo
. Nevertheless, some fundamental questions have yet to be answered. For example, the site (or sites) of MC and T cell cross-talk have not been convincingly demonstrated (e.g. site of inflammation, the lymphatic tissues, etc.) (). The advent and further development of novel technologies, such as intra-vital imaging, has the potential to shed light on such critical questions. MCs express a wide variety of molecules that act as positive and negative ligands for T cell activation and responses [21
] (). When are these molecules used in health and disease? Is there regulation of their expression on MCs in specific tissues? While it is clear that MCs possess the ability to both augment and to suppress inflammation, what is the relevance of this property to the role of the T cell in inflammation and to the development of potential therapies? It is hoped that the continued characterization of MC behavior in vivo
, in the setting of inflammation, will effectively address these fundamental issues and will shed new light on the role of the MC in immune regulation and its partnership with the T cell.