Age-related changes in murine T cell function

The aim of the studies presented here was to obtain a more detailed and integrated picture of the age-related changes in cellular immunity. The age-related changes of cellular immunity were studied by in vivo induction of DTH responses to a variety of antigens (Chapters 2 and 3). The results show that the capacity to elicit a DTH responses to SRBC, non H-2 and H-2 antigens declines during aging. This decline is observed in two mouse strains tested. Because the underlying causes of impaired DTH responsiveness are not easily studied in vivo, in vitro induction of DTH responses to H-2 antigens was studied (Chapter 3). It appeared that the CD4+ T cells give rise to the DTH reactive T cells and that the capacity of old mice to generate DTH reactive T cells in vitro is decreased. Since it was also shown that the IL-2 production ability of the mouse strains tested is impaired with increasing age (Chapter 2), the effect of the addition of exogenous IL-2 was studied. The decline in the capacity of cells from old mice to generate DTH reactive cells in vitro, however, could not be restored by addition of exogenous IL -2. More insight in possible causes for this age-related decrease of in vitro DTH responsiveness were obtained by studies on precursor frequency analysis of alloreactive CD4+ and CDS+ T cells in an MLR (Chapter 4). Especially, studies on the separate T cell populations were necessary, first since the in vitro induced DTH response is mediated by CD4+ T cells, secondly because possible suppressive effects exerted by CDS+ T cells on CD4+ T cells should be excluded. The results indicate that the alloreactive precursor frequency of both CD4+ and CDS+ T cells declines with increasing age. The observed decline in the frequencies can, however, not completely explain the reduced proliferative capacity observed in the MLR. It may be that there exists a defect at the level of signal transduction into the interior of the cell. Therefore, studies were performed, aimed at the process of signal transduction of CD4+ and CDS+ T cells. With the use of PMA and ionomycin, that bypass the TCR, the cells were activated and studied for some functional aspects like proliferative capacity, IL-2 production ability and IL-2 receptor expression (Chapter 5). It appeared that this type of activation in contrast to allogeneic stimulation resulted in comparable IL-2 production by CD4+ T cells from young and old mice. In contrast the proliferative responses of CD4+ T cells from old mice were lower than those from young mice, whereas the proliferative responses of CDS+ T cells from old mice were only slightly lower than those from young mice. Furthermore, the reduced capacity of CD4+ T cells to proliferate was not reflected by a reduced IL-2 receptor (IL -2R) expression. The IL-2R expression on CDS+ T cells was reduced on cells from old mice compared to cells from young mice. Therefore, it is most likely that the impaired immune responsiveness by T cells from aged mice is partly but not completely due to a reduced signal transduction process.

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