Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Microbiology and Immunology, 2007.
CD4+ T cells play multiple roles within the adaptive immune system. One of these
roles concerns the qualitative and quantitative modification of the CD8+ T cell
response, a phenomenon termed CD4 help. Although primary CD8 responses against
pathogens are largely independent of the presence of CD4+ T cells, responses directed
to cell-associated antigens show variable dependence on CD4 help. This variability is
likely a result of the different degrees of activation of the innate immune system
inherent in diverse models of immunization. Our laboratory has developed a
Dendritic Cell-based model of immunization that shows a strong dependency on CD4
help. We used this model and a traditional crosspriming system to test the hypothesis
that in pathogen-free systems, either inflammation or activation of NK cells would be
instrumental in the generation of primary CD8 responses in the absence of CD4 help.
Such immune responses could prove detrimental if resulting in unchecked expansion
of self-reactive CD8 T cells or beneficial in immunocompromised individuals with
deficient CD8 responses due to the lack of a functional CD4+ compartment. We
found that neither NK cell activation nor exposure to the inflammatory cytokine
TNF! was sufficient to bypass the requirement for CD4 help. However, a different
kind of signal, IFN!, proved to be enough to rescue CD8 responses in CD4-depleted
mice. Our results are in line with previous findings on the effects of IFN! on CD8
responses. The effects of inflammatory signals on CD4 differentiation were also
tested. Primed CD4+ T cells acquire distinct effector phenotypes, among them Th1
and Th2. A more recently described phenotype is characterized by the secretion of ILvi
2 and numerous chemokines, the expression of CD73 and the ability to further
differentiate into distinct committed phenotypes. To this date, the in vitro
differentiation of this cell subset has remained dependent on culture conditions that
also induce the expression of Foxp3+ regulatory T cells. Preliminary data in our
laboratory suggested that the combination of IL-6 and TGF" induced the
differentiation of IL-2 secreting cells while preventing the generation of regulatory T
cells. We formally tested the ability of these cytokines to induce the differentiation of
primed uncommitted CD4 cells. Cells primed by alloantigens under these conditions
expressed CD73 on their surface and differentiated into three main groups: IL-4
producers, IL-17 producers and IL-2 producers. After single cell sorting and cloning,
we found that the IL-2 producing subset showed similar “commitment” flexibility to
that shown by the previously described primed uncommitted cells.
