CD70 and Th17 Are Involved in Human Contact Sensitivity

October 2011 | Volume 10 | Issue 10 | Original Article | 1192 | Copyright © 2011

David S. Lee MD,a* Nicholas Gulati BA,b* Frank Martiniuk PhD,c William R. Levis MDd

aDepartment of Medicine, Mount Sinai School of Medicine, New York, NY bLaboratory for Investigative Dermatology, The Rockefeller University, New York, NY cDepartment of Medicine, Pulmonary Division, New York University School of Medicine, New York, NY dDepartment of Dermatology, New York University School of Medicine, New York, NY *Authors contributed equally to work

Abstract

CD70 (CD27L) has been shown to be preferentially expressed on Th1, but not Th2, CD4+ lymphocytes in murine contact sensitivity. The CD70-CD27 co-stimulatory pathway as well as the Th17 subset of lymphocytes have also been identified in human contact sensitivity reactions. The authors have previously reported increased expression of CD70 and the Th17-specific transcription factor retinoid orphan receptor gamma T in the elicitation phase of allergic contact dermatitis by reverse transcriptase-polymerase chain reaction. The manipulation of these pathways has potential for ameliorating autoimmune and inflammatory disorders such as allergic contact dermatitis, psoriasis and rheumatoid arthritis. Also, upregulation of the CD70-CD27 and Th17 pathways has been associated with the remarkable ability of topical sensitizers to treat warts and skin cancers including melanoma. As natural killer and natural killer T cells are also involved in contact sensitivity, future studies investigating the function of these cells are necessary to elucidate the transition between innate and acquired immune responses in the context of the Th1/Th2/Th17 and regulatory T cell paradigm.

J Drugs Dermatol. 2011;10(10):1192-1194.

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DISCUSSION

CD70 (CD27L) has recently been shown to be preferentially expressed on Th1, but not Th2, CD4+ lymphocytes in murine contact sensitivity.1 The CD70-CD27 co-stimulatory pathway as well as the Th17 subset of lymphocytes have also been identified in human contact sensitivity reactions.2,3 The authors have previously reported increased expression of CD70 and the Th17-specific transcription factor retinoid orphan receptor gamma T in the elicitation phase of allergic contact dermatitis (Figures 1 and 2).

Manipulation of these pathways has potential for ameliorating autoimmune and inflammatory disorders such as allergic contact dermatitis, psoriasis, psoriatic arthritis, and rheumatoid arthritis.4 Experimental treatment of murine collagen-induced arthritis and colitis with anti-CD70 antibody therapy has proven promising.5,6 Several biotechnology companies, including Seattle Genetics and Bristol-Myers Squibb, have already developed humanized anti-CD70 monoclonal antibodies and antibody-drug conjugates, which are currently being studied in the treatment of renal cell carcinoma and non-Hodgkin lymphoma in early-phase clinical trials. These agents also have the potential to treat autoimmune disorders.

Upregulation of the CD70-CD27 and Th17 pathways has been associated with the remarkable ability of topical sensitizers to treat warts and skin cancers including melanoma.7 CD70 and major histocompatibility complex class II localize in the late endosome and are jointly delivered to the immunological synapse at the cell surface, which is important for antigen-specific T cell activation.8 Activation of the CD70-CD27 co-stimulatory pathway has been implicated in adoptive transfer of interleukin 2-treated CD8+ T lymphocytes responsible for melanoma tumor regression.9 Byrne et al. recently reported durable CD8+ T lymphocyte immunity to melanoma in mice with vitiligo, strengthening the hypothesis that autoimmunity enhances antitumor immunity.10 Th17 cells, which have been shown to mediate destruction of advanced B16 melanoma in a transgenic mouse model,11 have been identified in the active margins of vitiligo lesions in humans.12 Given our current understanding of Th17 effector function, it is likely that this pathway enhances both neutrophil recruitment and CD8+ T cell killing activity in topical immunotherapy with contact sensitizers.

Natural killer T (NKT) cells are CD1d-restricted T cells that, in activated form, infiltrate the skin at elicitation sites of allergic contact dermatitis.13 In a murine model, activated NKT cells have been shown to be capable of inducing the expression of CD70 on dendritic cells.14 The presence or absence of CD27 differentiates two functionally distinct NK cell subsets. NK cells positive for this receptor have lower cytolytic potential than those that are negative. 15 Different NKT cell subsets also have been demonstrated to have important functional distinctions, especially with regards to tumor immunosurveillance. Classical type I or invariant NKT cells protect against tumor cell growth while type II NKT cells

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