CD4⁺ and CD8⁺ T cell priming for contact hypersensitivity occurs independently of CD40-CD154 interactions

The primary effector cells of contact hypersensitivity (CHS) responses to dintrofluorobenzene (DNFB) are IFN-γ-producing CD8⁺ T cells, whereas CD4⁺ T cells regulate the magnitude and duration of the response. The requirement for CD40-CD154 engagement during CD8⁺ and CD4⁺ T cell priming by hapten-presenting Langerhans cells (hpLC) is undefined and was tested in the current study. Similar CHS responses to DNFB were elicited in wild-type and CD154^-/- animals. DNFB sensitization of CD154^-/- mice primed IFN-γ-producing CD8⁺ T cells and IL-4-producing CD4⁺ T cells. However, anti-CD154 mAb MR1 given during hapten sensitization inhibited hapten-specific CD8⁺, but not CD4⁺, T cell development and the CHS response to challenge. F(ab′)₂ of MR1 failed to inhibit CD8⁺ T cell development and the CHS response suggesting that the mechanism of inhibition is distinct from that of CD40-CD154 blockade. Furthermore, anti-CD154 mAb did not inhibit CD8⁺ T cell development and CHS responses in mice depleted of CD4⁺ T cells or in CD4^-/- mice. During in vitro proliferation assays, hpLC from mice treated with anti-CD154 mAb during DNFB sensitization were less stimulatory for hapten-primed T cells than hpLC from either control mice or mice depleted of CD4⁺ T cells before anti-CD154 mAb administration. These results demonstrate that development of IFN-γ-producing CD8⁺ T cells and the CHS response are not dependent on CD40-CD154 interactions. This study proposes a novel mechanism of anti-CD154 mAb-mediated inhibition of CD8⁺ T cell development where anti-CD154 mAb acts indirectly through CD4⁺ T cells to impair the ability of hpLC to prime CD8⁺ T cells.