The role of Fcgamma receptor III (CD16) in the regulation of gammadelta T cells in multiple sclerosis

Multiple Sclerosis (MS) is an autoimmune central nervous system (CNS) disease characterized by inflammatory infiltrates alongside demyelinated axons, axonal transections and degenerating neurons; the exact mechanism whereby the immune system causes disease is still unclear. This lab has been exploring the possibility that innate immune responses are involved in disease immunopathogenesis, in particular gammadelta T cells which are concentrated in MS lesions. The work described in this thesis was undertaken to examine the possibility that gammadelta T cells, via their expression of CD16, mediate CNS injury by antibody dependent cell cytotoxicity (ADCC) and through the same encounter they release cytokines that regulate the immune responses. CD 16 is a low affinity Fcgamma receptor, an activation receptor for gammadelta T cells, and a mediator of cytotoxicity. In the first part of this study, I found that the number of CD16+ gammadelta T cells is elevated in MS patients compared with healthy controls. The increase is especially pronounced in patients with a progressive course, and the extent of this elevation shows a positive correlation with severity and duration. Secondly, two in vitro experimental systems were established to investigate the hypothesis that these CD16+ gammadelta T cells are capable of ADCC cytolysis. The results show that the cytotoxicity mediated by gammadelta T cells is significantly increased by the presence of a bridging antibody, and this effect could be abrogated by removal of Fc portion of antibody or by using CD16- effector cells, suggesting a CD16-specific antibody-mediated cytolytic contribution. This is the first study of its kind to confirm the ADCC capability of gammadelta T cells. Lastly, by using intracytoplasmic flow cytometry, I found that antibody-coated stimulant cells could induce production of cytokines from gammadelta T cells. Interestingly, the capability of producing Th2 cytokines exclusively resides in the CD16 + population, suggesting a regulative role of gammadelta T cells in the pathogenesis of MS. The findings of this work tie together the innate and adaptive immune responses through an interaction that involves the stimulation of antibody production, possibly against CNS molecules such as myelin, via CD 16 expressing gammadelta T cells that could use these antibodies to enact a guided attack on CNS targets via the mechanism of ADCC. This study offers further novel insights into the possible roles of gammadelta T cells in MS that can involve both potentially pathogenic and immunoregulatory functions