CD4+ and CD8+ T Cell Priming for Contact Hypersensitivity Occurs Independently of CD40-CD154 Interactions

Abstract

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.

CD4+ T Cells Regulate CD8+ T Cell-Mediated Cutaneous Immune Responses by Restricting Effector T Cell Development through a Fas Ligand-Dependent Mechanism

“…Consistent with previous reports from this laboratory (10,12), the magnitude and duration of CHS responses to DNFB were increased in mice depleted of CD4 ϩ T cells before hapten sensitization compared with responses in mice with the CD4 ϩ T cell compartment intact (Fig. 1A).…”

“…Recent studies from this laboratory indicated that CD4 ϩ T cells negatively influence the stimulatory capacity of LC during priming of hapten-specific CD8 ϩ T cells (12). These results led us to postulate that CD4 ϩ T cells may regulate CHS by restricting the development of effector CD8 ϩ T cells during hapten priming in the skin-draining lymph nodes.…”

“…As hapten-presenting DC prime both CD4 ϩ and CD8 ϩ T cells, these cells were logical targets of the CD4 ϩ T cell-mediated immunoregulation. Recent studies from this laboratory indicated that CD4 ϩ T cells may affect hapten-specific CD8 ϩ T cell development indirectly, via hapten-presenting DC (12). With these studies in mind, CD4 ϩ T cell-mediated regulation of DC presence in the lymph nodes during T cell priming for CHS was tested.…”

“…Recent studies suggested that CD4 ϩ T cells may attenuate DC activity during hapten-specific CD8 ϩ T cell priming (12). As hapten-presenting DC are the cells priming the effector CD8 ϩ T cells during sensitization for CHS, the numbers of hapten-bearing DC in the lymph nodes of sensitized control vs CD4 ϩ T cell-depleted mice were compared.…”

“…ELISPOT assays to enumerate IFN-␥-and IL-4-producing cells were performed as previously described (12). Briefly, ELISPOT plates (Unifilter 350; Polifiltronics, Rockland, MA) were coated with 100 l of 4 g/ml anti-IFN-␥ mAb R26A2 or anti-IL-4 mAb 11B11 and incubated overnight at 4°C.…”