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