All ETDs from UAB

Advisory Committee Chair

Allan J Zajac

Advisory Committee Members

André Ballesteros-Tato

David D Chaplin

Suzanne M Michalek

John D Mountz

Troy D Randall

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Protective immunity mediated by cellular and humoral immune responses relies on the ability of T cells and B cells to generate both effector cells that cooperate to eliminate antigens and memory cells that can survive for long periods with enhanced abilities to control recurring antigens. Thus, understanding the factors that regulate the development of T cell and B cell responses can improve the development of vaccines and immunotherapies against infectious diseases and cancers. Cytokines play important roles in regulating T cell and B cell responses, and in this thesis I have investigated the functions of two cytokines, interleukin (IL)-21 and IL-10, in the differentiation of various CD4 and CD8 T cell populations as well as germinal center (GC) B cells. We discovered that IL-21 acts directly on CD8 T cells to promote the differentiation, accumulation, and function of effector-phenotype CD8 T cell subsets including effector T (Te)/effector memory T (Tem) and tissue-resident memory T (Trm) cells under homeostatic and lymphopenic conditions. In addition, IL-21 is associated with increased expression of the chemokine receptor CX3CR1 and integrin α4β7 on CD8 T cells, which may influence their migration. Although acute lymphocytic choriomeningitis virus (LCMV) infection can offset these requirements for IL-21, memory virus-specific CD8 T cells still require IL-21 for their accumulation in tissues and sustained expression of CX3CR1 under lymphopenic conditions. In contrast to these stimulative effects of IL-21 on CD8 T cell differentiation, IL-10 functions during the priming phase of acute LCMV infection to suppress the development and functionality of memory virus-specific CD4 and CD8 T cells. Additionally, IL-10 influences the balance between antiviral Th1 and Tfh responses by suppressing the former. Nevertheless, neither the differentiation of GC B cells nor the production of LCMV-specific antibodies was influenced by the blockade of IL-10 signals. These findings further our understanding of the functions of IL-21 and IL-10 in regulating adaptive immune responses and highlight the therapeutic potentials of these two intriguing cytokines for the prevention and treatment of infectious diseases.

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