Selective role for the p55 Kd TNF-alpha receptor in immune unresponsiveness induced by an acute viral encephalitis.

ABSTRACT

Brain infection by the laboratory strain challenge virus standard (CVS), a highly neurotropic strain of rabies virus, causes splenocytes to become less responsive to in vitro stimulation with ConA. CVS-induced immune unresponsiveness is less severe in mice lacking the p55 Kd TNF-alpha receptor (p55TNFR(-/-)) than in C57BL/6 mice, despite a similar invasion of the brain. Comparison of CVS infection in these two strains of mice indicated that decreased immune responsiveness is associated with (1) an in vivo reduction of the percentages of Th1 (IL-2, IFN-gamma and TNF-alpha) but not of Th2 (IL-4) cytokine-secreting T cells; and (2) an in vivo increase of the percentages of CD25 and CD69-expressing splenocytes. In contrast, CVS-induced immune unresponsiveness is not associated with abnormal percentage of T, B, NK cells or monocytes in vivo. The reductions of the CD4/CD8 ratio and of splenocyte expression of I-A(b) during CVS infection are similar in p55TNFR(-/-) and C57BL/6 mice indicating that these two parameters are not linked to the decreased responsiveness of splenocytes. These data suggest that CVS-induced immune unresponsiveness is under the control of the p55 Kd TNF-alpha receptor. We propose that T cell activation through this receptor, in an environment of poor antigen presentation, results in a state of T cells characterized by the reduced production of IL-2, TNF-alpha and IFN-gamma in vivo, the decreased responsiveness of splenocytes to ConA stimulation in vitro and the expression of the activation markers CD25 and CD69.