gammadelta T cells derived from peripheral blood and cerebrospinal fluid of multiple sclerosis patients: Cytotoxic mechanisms, inhibitory natural killer cell receptors, and protein analysis

Multiple sclerosis (MS) is characterized by inflammation of the central nervous system, destruction of the oligodendrocyte/myelin unit, demyelination, and axonal loss. MS is believed to result from an autoimmune reaction mediated by alphabeta T cells against the myelin/oligodendrocyte unit. There is, however, increasing evidence that gammadelta T cells are also responsible for the damage observed in the MS brain: gammadelta T cells are found in increased numbers in the peripheral blood (PB) and cerebrospinal fluid (CSF) of MS patients, accumulate in MS lesions, and lyse oligodendrocytes in vitro. The cytotoxic mechanism(s) utilized by gammadelta T cells and the control of these mechanisms are incompletely understood, although it has been reported that gammadelta T cell mediated cytotoxicity can be regulated via inhibitory natural killer cell receptors (iNKR).; The work described in this thesis was undertaken to gain a more complete understanding of the cytotoxic mechanism(s) utilized by gammadelta T cells, to investigate the control of gammadelta T cell mediated cytotoxicity by iNKR, and to search for differences in cytotoxic phenotype and function between PB and CSF derived gammadelta T cells.; My results have demonstrated that gammadelta T cell mediated cytotoxicity proceeds via the perform/granzyme and Fas/FasL pathways, that granzyme B is an especially potent cytotoxic mediator for these cells, and that the exact method of attack is influenced by the target cell. As well, the cytotoxicity mediated by gammadelta T cells cannot be modulated solely via manipulation of the iNKR/HLA class I molecule interaction, but instead is under the control of a number of inhibitory and activating receptors. It is the balance of the signals these receptors generate that determines the action of the gammadelta T cell. A number of functional and phenotypic differences were observed between PB and CSF derived cells. Two dimensional electrophoretic analyses of protein isolated from PB and CSF derived gammadelta T cells revealed an MS CSF specific protein "profile" consisting of 7 proteins absent from the MS CSF samples.