Nickel-specific CD4+ and CD8+ T cells display distinct migratory responses to chemokines produced during allergic contact dermatitis

Abstract

Development of allergic contact dermatitis to haptens depends upon a balance between CD8+ T lymphocytes with pathogenic activity and CD4+ T cells, which comprise both effector and regulatory cells. Thus, differential recruitment of CD8+ and CD4+ lymphocytes to sites of hapten challenge may have considerable impact on disease expression. Here the migration of cutaneous lymphocyte-associated antigen+, nickel-specific CD8+ and CD4+ T cell lines were compared with a panel of chemokines produced in the skin during allergic contact dermatitis. CCL17/TARC and CCL22/MDC induced a 3-fold higher migration of CD4+ compared with CD8+ lymphocytes. In contrast, CXCL10/IP-10 was 2-fold more potent in attracting CD8+ cells. These findings were consistent with the higher expression of CCR4 and CXCR3 on CD4+ and CD8+ T cell lines, respectively. Moreover, CCR4 expression was high on nickel-specific T helper 2, intermediate on T helper 1 and T cytotoxic 2, and almost undetectable on T cytotoxic 1 clones. On the contrary, CXCR3 was expressed by T cytotoxic 1 and 2 and T helper 1, but not T helper 2 clones. Reverse transcription-polymerase chain reaction analysis of the skin before and after hapten challenge revealed the constitutive presence of TARC, and the early appearance of CCL2/MCP-1, followed by IP-10, CCL4/MIP-1β, and MDC mRNA. Supernatants from activated keratinocytes induced a strong migration of CD8+ lymphocytes, which was blocked by neutralization of IP-10. Conversely, supernatants from immature and mature dendritic cells attracted mostly CD4+ lymphocytes in a TARC- and MDC-dependent manner. Our data indicate that distinct chemokines and cell types control the accumulation of CD8+ and CD4+ T cells within inflamed skin.