IntroductionThe role of CD4 ϩ cells in antitumor immunity remains controversial and poorly understood. 1,2 They are known to mediate potent therapeutic effect in the setting of hematopoietic stem cell allotransplantation and donor lymphocyte infusion in hematologic malignancy, 3,4 but antigen-specific T helper (Th) cells have been studied to much lesser extent. A lack of clarity regarding CD4 ϩ cells is due, in no small part, to the complexity of their biology. CD4 ϩ T cells can differentiate into diverse subsets with specific phenotypes that can have self-reinforcing and opposing functions, but these T-cell subsets have not been comprehensively studied in tumor-bearing mice.Historically, CD4 ϩ T lymphocytes have been thought of as mere providers of stimuli to help the putatively more important CD8 ϩ effectors, which eliminate cancer by direct cytotoxicity. [5][6][7] There are several studies showing that CD4 ϩ T helper (Th) cells are capable of protecting the host against tumor challenge and even of mediating tumor regression on their own in the setting of either solid or hematopoietic disease. [8][9][10][11][12][13] Furthermore, protection was maintained against MHC class II-negative multiple myeloma model and involved cross-presentation by professional antigenpresenting cells (APCs) and activation of tumoricidal activity mediated by macrophages secreting IFN-␥. 14 A similar IFN-␥-dependent mechanism was involved in the rejection of MHC class II-negative tumor in severe combined immunodeficient (SCID) mice. 15 In some cases, the ability to reject antigen-expressing tumor by specific naive Th cells was thought to be substantially better than the ability of CD8 ϩ cells. 16 Classically, effector CD4 ϩ T cells have been categorized into T helper 1 (Th1) and T helper 2 (Th2) subsets. 17,18 Limited studies indicate that both subtypes elicit antitumor effects, 19-21 but the Th1-polarized cells, secreting IFN-␥ and capable of enhancing activity of cytotoxic CD8 ϩ lymphocytes, have traditionally been regarded as more efficient. [22][23][24][25] However, it is also clear that CD4 ϩ T regulatory cells (T regs ) can efficiently suppress the function of antitumor CD8 ϩ T cells. 5,[26][27][28] Recently, the novel Th17 lineage, generated in the presence of TGF-␤ and IL-6 and expanded under the influence of IL-23, [29][30][31] has been associated with responses against certain infections and implicated in the development of autoimmunity in animal models that had been previously linked to Th1-type responses (experimental autoimmune encephalitis, collagen-induced arthritis). 32,33 They also seem to play an important role in the pathogenesis of graft-versus-host disease (GVHD). 34,35 Th17 cells have been found in various tumors, including mycosis fungoides, Sézary syndrome, and prostate cancer. 36,37 Kryczek et al reported the presence of naturally occurring Th17 cells and T regs in the tumor microenvironment and tumor-draining lymph nodes in both human and mice tumors. 38 Proinflammatory cytokines including IL-17A, IL-6, and I...

Many human and mouse tumor antigens are normal, nonmutated tissue differentiation antigens. Consequently, immunization with these ''self'' antigens could induce autoimmunity. When we tried to induce immune responses to five mouse melanocyte differentiation antigens, gp100, MART-1, tyrosinase, and tyrosinase-related proteins (TRP) 1 and TRP-2, we observed striking depigmentation and melanocyte destruction only in the skin of mice inoculated with a vaccinia virus encoding mouse TRP-1. These mice rejected a lethal challenge of B16 melanoma, indicating the immune response against TRP-1 could destroy both normal and malignant melanocytes. Cytotoxic T lymphocytes specific for TRP-1 could not be detected in depigmented mice, but high titers of IgG anti-TRP-1 antibodies were present. Experiments with knockout mice revealed an absolute dependence on major histocompatibility complex class II, but not major histocompatibility complex class I, for the induction of both vitiligo and tumor protection. Together, these results suggest that the deliberate induction of self-reactivity using a recombinant viral vector can lead to tumor destruction, and that in this model, CD4؉ T lymphocytes are an integral part of this process. Vaccine strategies targeting tissue differentiation antigens may be valuable in cancers arising from nonessential cells and organs such as melanocytes, prostate, testis, breast, and ovary.