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Faculty Adam J. Adler
Associate Professor of Immunology
Associate Director, Graduate Program in Immunology
aadler@up.uchc.edu
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.
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