T cell mediated immunity in malaria and mycobacterial infection : a protective role for gd+ T cells

Abstract

T cell mediated immunity is essential against intracellular infections. Studies of cell mediated immunity are important for the optimal design and development of effective vaccines. Identifying correlates of protective immunity will also enable measurement of vaccine efficiency. This thesis includes studies of T cell mediated immune protection against malaria and mycobacterial infections. A major focus of this work was the investigation of the role of [gamma][delta]+ T cell responses. In an initial study of lymphocyte subset compositions, a higher percentage of cytotoxic T cells were found in the peripheral blood of healthy adults from Ethiopia and Bangladesh than from Sweden. This suggested the involvement of environmental and/or genetic factors on the adaptation of the cellular immune system. During acute malaria illness there was a complex pattern of changes in lymphocyte subset distribution and activation that appeared to be different in P. falciparum infection compared to P. vivax. During acute P. falciparum illness an increase in level and activation of [gamma][delta]+ T cells, that was mostly due to increase in V[delta]1+ cells was found. However, during both infections increased numbers of CD4+, CD8+ and [gamma][delta]+ T cells in peripheral blood were expressing the proliferation marker Ki-67. These results suggest that all T cells are activated and that lymphocyte redistribution and /or activation driven apoptosis may be the cause of the altered phenotypic profiles in peripheral blood. An in vitro assay was developed to study the functional significance of [gamma][delta]+ T cells. Generally activated [gamma][delta]+ T cells of both V[delta]1+ and V[delta]2+ subsets but not similarly activated [alpha][beta] T cells from non-malaria exposed individuals inhibited the in vitro growth of asexual blood stages of P. falciparum parasite. The inhibition was correlated to the number of [gamma][delta]+ T cells and required cell-to-cell contact. Kinetic analysis suggested the likely targets to be the late infected erythrocyte (schizonts) or extracellular merozoites. These results suggest [gamma][delta]+ T cells may have a protective role during malaria infection independent of previous exposure to malaria. An in vitro assay was also developed to measure T cell mediated inhibition of mycobacterial growth. Both [alpha][beta]+ and [gamma][delta]+ T cells from PPD positive individuals inhibited intracellular growth of BCG, but only when activated by mycobacterial antigens. The mycobacterial growth inhibition capacity was up regulated by BCG vaccination and required cell-to-cell contact. These results suggest a role for [gamma][delta]+ T cells in the memory responses against mycobacteria. Expressions of proinflammatory cytokines and cytolytic molecules such as perforin, granzymes, granulysin and Fas/Fas ligand, were characteristic of both malaria and BCG growth inhibitory T cells. However, expression of these molecules in non-inhibitory activated cells were also seen, suggesting that growth inhibition requires restricted recognition of target cells by specific effectors. Our results indicate that [gamma][delta]+ T cells may represent an important component of the primary immune defense against P. falciparum infection and the memory immune defense against mycobacterial infection