Indirect regulation of CD4 T-cell responses by tumor necrosis factor receptors in an acute viral infection.
Despite the well-recognized importance of CD4 T-cell help in the induction of antibody production and cytotoxic-T-lymphocyte responses, the regulation of CD4 T-cell responses is not well understood. Using mice deficient for TNF receptor I (TNFR I) and/or TNFR II, we show that TNFR I and TNFR II play redundant roles in down regulating the expansion of CD4 T cells during an acute infection of mice with lymphocytic choriomeningitis virus (LCMV). Adoptive transfer experiments using T-cell-receptor transgenic CD4 T cells and studies with mixed bone marrow chimeras indicated that indirect effects and not direct effects on T cells mediated the suppressive function of TNF on CD4 T-cell expansion during the primary response. Further studies to characterize the indirect effects of TNF suggested a role for TNFRs in LCMV-induced deletion of CD11c(hi) dendritic cells in the spleen, which might be a mechanism to limit the duration of antigenic stimulation and CD4 T-cell expansion. Consequent to enhanced primary expansion, there was a substantial increase in the number of LCMV-specific memory CD4 T cells in the spleens of mice deficient for both TNFR I and TNFR II. In summary, our findings suggest that TNFRs down regulate CD4 T-cell responses during an acute LCMV infection by a non-T-cell autonomous mechanism.
Singh
Anju
A
Department of Pathobiological Sciences, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA.
Wüthrich
Marcel
M
Klein
Bruce
B
Suresh
M
M
D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000821:virology; D014777:Virus Diseases / Q000097:blood*
D018960:Hyaluronan Receptors; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins