While the presence of memory T cells specific for pathogens is beneficial in providing protective immunity, generation of memory T cells can be deleterious if directed against self antigens in autoimmune disease, and against alloantigens in transplantation.  Our longstanding interests in mechanisms and strategies for modulation of memory CD4 T cell responses (5, 10, 11), based on our initial finding that memory T cell exhibit functional plasticity (12), has prompted studies examining memory T cell development and function in autoimmunity and alloimmunity.  We have set up new models to investigate memory in these clinically relevant contexts.  

In transplantation, the presence of alloreactive memory T cells is associated with increased episodes of acute rejection and resistence to immunosuppression and tolerance induction regimens (13, 14).  However, the susceptibility of memory T cells to immunosuppressants in vivo and their propensity for allograft rejection has not been characterized.  In order to address these important issues in transplantation,  we set up a model to track a population of alloreactive memory CD4 T cells, using a modification of an in vitro-priming adoptive transfer technique, resulting in  “mosaic-memory mice” (15). Using this model, we also found that memory CD4 T cells are susceptible to T cell depletion using anti-thymocyte globulin (Thymoglobulin, Genzyme, Inc.), which is a commonly used T cell induction agent. We followed the dynamics of reconstitution by naive and memory CD4 T cells in the presence or absence of a thymus, and found that contrary to what was previously thought from clinical studies, naive CD4 T cells undergo the greatest increase in homeostatic proliferation following thymoglobulin-mediated depletion, compared to memory T cells.  Moreover, while memory CD4 T cell homeostasis following T cell depletion was comparable in thymectomized and euthymic mice, homeostatic proliferation of naive CD4 T cells was greatest following depletion in thymectomized hosts, with thymic output in euthymic hosts suppressing naive CD4 T cell homeostasis (Sener, A. ,Tang, AL and Farber,DL, manuscript in preparation).  These findings of spontaneous proliferation of naive CD4 T cells following thymoglobulin induction therapy, particularly in situation of low thymic output (as would be the case with most transplant patients aged 45-60years), could potentially lead to inappropriate immune activation or dysregulation.  Our future plans are to investigate the TCR and cytokine requirements this post-depletion T cell homeostasis induced by thymoglobulin, and the effects of calcineurin inhibitors and other immunosuppressants in this process, to model the clinical situation.  We also would like to determine the effect of thymoglobulin depletion on thymic output, of relevance to using this drug in younger patients.  These studies represent a mechanistic approach to analyzing a clinically relevant issue of T cell depletion and reconstitution, and can also lead to translational analysis of human T cell reconstitution early after thymoglobulin treatment. These studies are currently supported by a grant from the Roche Organ Transplant research foundation (ROTRF).  

In autoimmunity, memory T cells can theoretically be generated in response to autoantigens; however, memory CD4 T cell generation to autoantigens has not been assessed.  In type I diabetes mellitus, autoreactive CD4 T cells are known to initiate disease, and we are using a diabetes model to assess whether islet-reactive effector CD4 T cells can develop into memory CD4 T cells. In studies supported by a new research grant from the juvenile diabetes research foundation (JDRF), we have  examined memory CD4 T cell persistence in the NOD diabetes model and a model in which TCR-transgenic CD4 T cells specific for an islet neoantigen (influenza HA) can infiltrate the islets.  We are particularly interested if islet-infiltrating effector cells develop into memory CD4 T cells with a propensity to home to islets.  We are also investigating the role of lymphopenia in the development and homing of islet-reactive memory CD4 T cells.