Maintenance of immune fitness during reconstitution from T cell lymphopenia by CD4-positive, CD25-positive, and Foxp3-positive regulatory T cells.

Abstract

Work presented in this doctoral thesis focuses on the role of regulatory T cells (Tregs) in controlling T cell homeostasis and emergence of autoimmunity during immune reconstitution from lymphopenia. It is recognized that lymphopenia may be a common trigger of many autoimmune diseases due to oligoclonal expansion of self-reactive T cells with an effector phenotype. It is also a clinical fact that autoimmunity is often associated with immune deficiency and poor responsiveness to vaccines and infections. Research supporting work presented in chapter 2 of this thesis was based on the hypothesis that poor Treg function may play a central role in these phenomena. This work, published in June of 2008 in the Journal of Immunology, clearly demonstrated that Tregs selectively restrain one specific form of lymphopenia-induced proliferation characterized by burst-like cell cycle activity and effector T cell differentiation (spontaneous proliferation). The spontaneous form of lymphopenia-induced proliferation is the likely source of oligoclonal expansion of self-reactive T cells that drive autoimmunity. Work presented in chapter 3 of this thesis addresses the hypothesis that such oligoclonal expansion by a few T cell clones consumes resources away from the rest of the T cell population, which ultimately results in loss of T cell diversity. Using the technique of T cell adoptive transfer, we measured immune responses to infection with the gram negative bacteria Listeria monocytogenes in lymphopenic mice reconstituted in the presence or absence of Tregs by analysis of T cell receptor (TCR) Vbeta chain usage and repertoire sampling using Vbeta-Jbeta chain TCR spectratyping and magnetic bead enrichment with specific major histocompatibility (MHC) class I and II tetramers. Experimental results suggest that the presence of Tregs during immune reconstitution preserves TCR structural diversity and allows for more accumulation of pathogen-associated antigen-specific T cells in secondary lymphoid tissues following clearance of the infection. This result may otherwise seem paradoxical as Tregs are typically thought of as generalized suppressors of the immune system. Regardless, we believe this unappreciated ability to maintain T cell homeostasis through preservation of peripheral diversity will shed considerable insight into the role of Tregs in the immune system, vaccine responsiveness, pathogenesis of autoimmunity, and immune senescence.