The roles and control of CD4+ effector and regulatory T cells in biliary autoimmunity

Webb, Gwilym James ORCID: 0000-0002-0710-5644 (2019). The roles and control of CD4+ effector and regulatory T cells in biliary autoimmunity. University of Birmingham. Ph.D.

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Abstract

Autoimmunity represents a misdirection of the adaptive immune response against the self. The pre- valence of human autoimmunity is increasing, including an increasing prevalence of autoimmune liver disease. Novel therapeutic options are required and failure of the regulation of CD4+ T cells has been implicated in pathogenesis. OX40, ligated by OX40L, is a secondary co-stimulatory molecule which promotes activation and survival of CD4+ T cells and has been proposed as a therapeutic target in autoimmunity and regulatory failure.

Complete deficiency in FOXP3-positive regulatory T cells results in a lymphocytic hepatitis associated with autoantibodies and loss of effector CD4+ T cell control. This thesis confirms this finding and demonstrates similar pathology in mice deficient in the regulatory molecule CTLA4 and in Roquin sanroque mutant mice. Each of these mouse models is shown to hyperexpress OX40 on liver-infiltrating CD4+ T cells. In FOXP3 deficiency, blockade of OX40-OX40L interactions abrogates hepatitis; whereas in CTLA4 deficiency and the Roquin sanroque mutant mouse, OX40-OX40L blockade is ineffective.

Complementary to these findings, increased expression of OX40 is demonstrated in human autoim- mune liver disease, and a negative regulatory mechanism on the expression of OX40L by T cells by the action of gamma-chain cytokines including interleukin-2 is described.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):