When mature T cells encounter their cognate antigens they must make a critical decision: do these antigens derive from pathogens (in which case the T cells must be primed to express effector functions that facilitate pathogen neutralization), or do these antigens derive from the bodies own healthy tissues (in which case the T cells must be rendered tolerant (i.e. non-responsive) so that they will not induce autoimmunity)?

To study how CD4+ helper T cells make this decision, we have developed a transgenic mouse model system to compare the response of CD4 cells specific for the model antigen HA when it is expressed either as a peripheral (i.e. non-lymphoid) self-antigen, or as a viral-antigen. Upon encountering viral-HA, naive CD4 cells are primed to proliferate and develop an effector/memory phenotype (i.e., the capacity to undergo further proliferation and secrete effector cytokines when re-stimulated with HA). Although naive CD4 cells encountering peripheral self-HA also undergo an initial proliferative response, they ultimately become tolerant (i.e., non-responsive to further stimulation). Previous work from many laboratories has shown that T cell priming to pathogen-derived antigens is mediated by bone marrow-derived antigen presenting cells (APCs) that have acquired these antigens from infected tissues and then presented them to cognate T cells (a process termed "cross-priming"). Interestingly, we have found that CD4 cell tolerance induction to self-HA is also mediated indirectly by APCs that have acquired HA from peripheral HA-expressing tissues (a process termed "cross-tolerization"). Thus, APCs play the pivotal role in determining how T cells distinguish pathogen-derived from peripheral self-antigens. Our more recent data indicates that qualitatively distinct APC-delivered signals program CD4 cell tolerization versus priming to self-HA and viral-HA, respectively, but that these initial programming events can be reversed; effector CD4 cells primed by viral-HA can be tolerized upon contact with tolerogenic APCs presenting self-HA. This reprogramming might represent a mechanism that helps to minimize the amount of autoimmune damage that ensues following infection with pathogens that express antigens that are cross-reactive with self (i.e., molecular mimicry), and might also limit the effectiveness of T cell-based therapies to treat cancer. We are currently studying this effector CD4 cell tolerization pathway using both cellular and molecular approaches.

Our lab is also interested in studying the immunological properties of prostate cancer (the most common malignancy in American men). In transgenic mice that express HA specifically in the prostate, HA-specific CD4 cells do not undergo tolerization, presumably because HA is sequestered from the draining lymphatics and cross-tolerizing APCs. When these mice develop prostate cancer, however, the same CD4 cells undergo tolerization. Interestingly, if mice that have developed prostate tumors receive androgen-blockade (the standard treatment for advanced prostate cancer), the tolerogenic potential of these tumors is mitigated. Current efforts are directed towards utilizing this knowledge to develop therapeutic strategies to treat prostate cancer.

Higgins AD, Mihalyo MA, McGary PA and Adler AJ, 2002. CD4 Cell priming and tolerization are differentially programmed by APCs upon initial engagement. J. Immunol. 168:5573-5581.

Higgins AD, Mihalyo MA and Adler AJ, 2002. Effector CD4 Cells are Tolerized Upon Exposure to Parenchymal Self-Antigen. J. Immunol. 169:3622-3629.

Long M, Higgins AD, Mihalyo MA and Adler AJ, 2003. Effector CD4 cell tolerization is mediated through functional inactivation and involves preferential impairment of TNF-a and IFN-g expression potentials. Cell. Immunol. 224:114-121.

Mihalyo MA, Doody ADH, McAleer JP, Nowak EC, Long M, Yang Y and Adler AJ, 2004. In vivo cyclophosphamide and IL-2 treatment impedes self-antigen-induced effector CD4 cell tolerization: implications for adoptive immunotherapy. J. Immunol. 172:5338-5345.

Doody ADH, Kovalchin JT, Mihalyo MA, Hagymasi AT, Drake CG and Adler AJ, 2004. Gp96 can chaperone both MHC class I and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function. J. Immunol. 172:6087-6092.

Drake CG, Doody ADH, Mihalyo MA, Huang C-T, Kelleher E, Ravi S, Hipkiss EL, Flies DB, Kennedy EP, Long M, McGary PW, Coryell L, Nelson WG, Pardoll DM, and Adler AJ, 2005. Androgen ablation mitigates tolerogenic presentation of a prostate/prostate cancer-restricted antigen. Cancer Cell 7:239-249.

Adler AJ, 2005. Peripheral tolerization of effector and memory T cells: implications for autoimmunity and tumor-immunity. Curr. Immunol. Rev. 1:21-28.

Long M, Slaiby AM, Hagymasi AT, Mihalyo MA, Lichtler AC, Reiner SL and Adler AJ, 2006. T-bet down-modulation in tolerized Th1 effector CD4 cells confers a TCR-distal signaling defect that selectively impairs IFN-g expression.  J. Immunol. 176:1036-1045.

Adler AJ. Mechanisms of T Cell Tolerance and Suppression in Cancer Mediated by Tumor-Associated Antigens and Hormones. Curr. Cancer Drug Targets (in press)