|
|
 |
|
|
 |
 |
|
|
|
Adam J. Adler, Ph.D.
Associate Professor
Member of the Immunology and Developmental Biology Graduate Programs
Email:
aadler@up.uchc.edu
|
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.
In a related project, we are studying how heat shock proteins (HSPs) regulate T cell tolerance versus immunity. It has been well established that when HSPs are released from cells, they can bind to surface receptors on dendritic cells which allows the peptides that are naturally associated with HSPs to be presented by MHC class I molecules. This interaction also induces dendritic cell activation/maturation, and thus facilitates the priming of cognate effector CD8 cell responses (i.e., cross-priming). This pathway can be exploited to elicit effector CD8 cell responses directed towards both tumors and pathogens. We recently assessed whether the HSP gp96 can facilitate the presentation of MHC class II-restricted peptides and prime cognate CD4 cell responses in vivo, and made the unexpected finding that while gp96 can deliver peptides into the MHC class II presentation pathway, the resulting CD4 cell responses do not involve the development of effector functions. This result has a number of interesting implications regarding the regulation of T cell tolerance versus immunity, which we are currently testing.
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.
Selected Publications
- Adler AJ, Marsh DW, Yochum GS, Guzzo JL, Nigam A, Nelson WG and Pardoll DM, 1998. CD4+ T Cell Tolerance to Parenchymal Self Antigens Requires Presentation by Bone Marrow Derived Antigen Presenting Cells. The Journal of Experimental Medicine 187:1555-1564.
- Adler AJ, Huang C-T, Yochum GS, Marsh JL and Pardoll DM, 2000. In vivo CD4+ T cell tolerance induction versus priming is independent of the rate and number of cell divisions. The Journal of Immunology 164:649-655.
- Higgins AD, Mihalyo MA, McGary PA and Adler AJ, 2002. CD4 Cell priming and tolerization are differentially programmed by APCs upon initial engagement. The Journal of Immunology 168:5573-5581.
- Higgins AD, Mihalyo MA and Adler AJ, 2002. Effector CD4 Cells are Tolerized Upon Exposure to Parenchymal Self-Antigen. The Journal of Immunology 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. Cellular Immunology 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. The Journal of Immunology 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. The Journal of Immunology 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. Current Immunology Reviews 1:21-28.
|
|
|
|
|
|
|
|
Send comments or questions to:
Phone: 860-679-4444 Fax: 860-679-7905
Center for Immunotherapy of Cancer and Infectious Diseases
University of Connecticut Health Center
263 Farmington Avenue
Farmington, Connecticut 06030-1601
Copyright 2001 University of Connecticut Health Center
Web site developed by
|
|
|
|
