Areas of Interest
When a mature T cell encounters its cognate antigen it must make a critical decision: does the antigen derive from a pathogen (in which case the T cell must be primed to express
effector functions in order to neutralize the pathogen), or does the antigen derive from the bodies own healthy tissues (in which case the T cell must be rendered tolerant (i.e.,
non-responsive) so that it 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 antigen HA when HA is
expressed either as a peripheral (i.e., non-lymphoid) self-antigen, or as a viral-antigen. Upon encountering viral-HA, the CD4 cells proliferate, and subsequently develop an effector/memory
phenotype (i.e., the capacity to undergo further proliferation and to secrete effector cytokines when re-exposed to HA). Although 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 antigens from
peripheral self-antigens. Our most current data indicates that functionally distinct tolerogenic and immunogenic APCs present parenchymal-self-HA and viral-HA to program CD4 cell
tolerization and priming, respectively. Interestingly, these initial programming events can be reversed, as viral-HA-primed effector/memory CD4 cells 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 induced by pathogens that express antigens that
are cross-reactive with self. We are currently studying the molecular mechanisms that render CD4 cells non-responsive, as well as the pathways by which different antigens are
cross-presented, and how these pathways might influence immunogenic versus toleragenic APC activity. Ultimately, these studies will provide insight into how immune responses can be
manipulated to treat diseases in which it is desirable to either induce tolerance (e.g., autoimmunity or transplantation) or to block or reverse it (e.g., cancer).
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. Interestingly, when these
mice either develop prostate cancer, or when they are castrated (a common treatment for prostate cancer which induces degeneration of the prostate), the same CD4 cells undergo
tolerization. These results have important implications for how prostate tumor vaccines might be effectively administered.
Lab Rotation Projects
Projects studying the regulation of T cell tolerance and immunity
#1 – Study the role of different accessory cells in inducing the tolerization of effector CD4 cells to self-antigen.
We have found that Th1 effector CD4 cells undergo tolerization when exposed to self-antigen, which likely has important implications for understanding the dynamics of autoreactive T
cell responses. We have also found that bone marrow-derived antigen presenting cells (APCs) play a critical role in this process, and the current project will utilize various transgenic
mice to determine whether dendritic cells (DCs) constitute the relevant APCs sub-population that induces tolerization. Additionally, the potential role of regulatory T cells (Tregs) in
facilitating tolerization will also be examined.
#2 – Explore the relationship between heat shock proteins (HSPs), T cell priming versus tolerance induction, and autoimmunity.
We have previously found that immunization with soluble HSP-peptide complexes prime cognate naïve CD8 cells, but not naïve CD4 cells, to develop effector function. Paradoxically,
other studies have indicated that in vivo extra-cellular expression of HSPs results in the development of autoimmunity that is dependent on CD4 but not CD8 cells. The current project
will use a combination of different transgenic mouse models to resolve this paradox, and ultimately better understand the relationship between HSPs, T cell priming versus tolerance
induction, and autoimmunity.
Selected Publications
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 tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell 7:239-49.
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. Glycoprotein 96 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.
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- and IFN-
expression potentials. Cell. Immunol. 224:113-120.
Higgins AD, Mihalyo MA and Adler AJ, 2002. Effector CD4 cells are tolerized upon exposure to parenchymal self-antigen. J. Immunol. 169:3622-3629. |
