Publication Date

2014-07-10

Availability

Embargoed

Embargo Period

2016-07-09

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2014-06-30

First Committee Member

Zhibin Chen

Second Committee Member

Thomas Malek

Third Committee Member

Samita Andreansky

Fourth Committee Member

Jacob McCauley

Fifth Committee Member

Eric Greidinger

Sixth Committee Member

Kurt Schesser

Seventh Committee Member

Cherie Stabler

Abstract

Immunological memory is a hallmark of adaptive immunity, a defense mechanism endowed to vertebrates during evolution. However, an autoimmune pathogenic role of memory lymphocytes is also emerging with accumulating evidence. It is conceivable that autoimmune memory would be particularly harmful since memory cells would “constantly remember” and attack the body’s healthy tissues. It is even more detrimental given the resistance of memory T cells to immunomodulatory therapies. On the other hand, with their long-lasting potency the autoimmune memory cells could also play a critical role in anti-tumor immunity, which may be largely based on their reactivity to self-antigens. In this dissertation, I will discuss the role of autoimmune CD4+ effector memory T cells (TEM) in chronic and acute infectious disease settings while presenting to you evidence on their pathogenicity in autoimmune disease. Quantitative variations in CTLA4 expression, due to genetic polymorphisms, are associated with various human autoimmune conditions, including type 1 diabetes (T1D). Extensive studies have demonstrated that CTLA4 is not only essential for the suppressive role of regulatory T (Treg) cells, but also required for intrinsic control of conventional T (Tconv) cells. We report that a modest insufficiency of CTLA4 in mice, which mimics the effect of some human CTLA4 genetic polymorphisms, accompanied by a T1D-permissive MHC locus, was sufficient to induce juvenile-onset diabetes on an otherwise T1D-resistant genetic background. Reduction in CTLA4 levels had an unanticipated effect in promoting Treg cell function both in vivo and in vitro. This cell-intrinsic impact of CTLA4 reduction in Treg cells led to an increase in Treg memory in both lymphoid and nonlymphoid target tissue. Conversely, modulating CTLA4 by either RNAi or antibody blockade promoted TEM formation in the Tconv compartment. The CD4+ TEM cells, including those within target tissue, produced IL17 or IFNγ. Blocking IL7 signaling reduced the Th17 autoimmune compartment, but did not suppress the T1D induced by CTLA4 insufficiency. Enhanced effector memory formation in both Tconv and Treg lineages may underpin the apparently dichotomized impact of CTLA4 insufficiency on autoimmune pathogenesis. Therefore, while the presence of CTLA4 plays a critical role in controlling homeostasis of T cells, its quantitative variation may impose diverse or even opposing effects on distinct lineages of T cells, an optimal sum of which is necessary for preservation of T-cell immunity while suppressing tissue damage. Variations in CTLA4 splicing have been implicated in several gene polymorphisms that increase susceptibility to T1D. We established an in-vitro system to study the effects of reduction in specific splice variants levels of CTLA4, using lentiviral RNAi technology, in human T cells. There was an increased proliferation of CD4+ T cells on a reduction in the ¼CTLA4 splice variant akin to the effects caused by a reduction in sCTLA4 (soluble CTLA4) and FlCTLA4 (full-length CTLA4) splice variants. This data is intriguing in light of the recently published study that suggests that the functions of ¼CTLA4 are opposite to that of FlCTLA4 and sCTLA4. This system generated interesting preliminary data and has the potential to be used further to explore a number of questions pertaining to the role of CTLA4 splice variants with physiological relevance to T cell responses in human disease.

Keywords

Type 1 Diabetes; autoimmune memory; CTLA4; splice variants; regulatory memory; effector memory

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