Human MHC class I-related molecules, MICA and MICB, are stress-induced antigens that are recognized by a subset of ␥␦ T cells expressing the variable region V ␦ 1. This functional association has been found to be limited to intestinal epithelium, where these T cells are prevalent and where MICA and, presumably, MICB are mainly expressed. However, increased frequencies of V ␦ 1 ␥␦ T cells have been observed in various epithelial tumors; moreover, MICA͞B are expressed on diverse cultured epithelial tumor cells. With freshly isolated tumor specimens, expression of MICA͞B was documented in many, but not all, carcinomas of the lung, breast, kidney, ovary, prostate, and colon. In tumors that were positive for MICA͞B, the frequencies of V ␦ 1 ␥␦ T cells were significantly higher than in those that were negative. V ␦ 1 ␥␦ T cell lines and clones derived from different tumors recognized MICA͞B on autologous and heterologous tumor cells. In accord with previous evidence, no constraints were observed in these interactions, such as those imposed by specific peptide ligands. Thus, MICA͞B are tumor-associated antigens that can be recognized, in an apparently unconditional manner, by a subset of tumor-infiltrating ␥␦ T cells. These results raise the possibility that an induced expression of MICA͞B, by conditions that may be related to tumor homeostasis and growth, could play a role in immune responses against tumors.Cytolytic T cell responses against tumors require the recognition of specific peptides derived from tumor antigens in association with MHC class I molecules by CD8 ϩ T cells expressing ␣␤ T cell receptors (TCRs). Such responses are limited by antigenic peptides (1), which must be generated by intracellular antigen processing (2), by their highly selective binding to only some of the numerous polymorphic MHC class I molecules (3), and by the often-impaired expression of MHC class I on tumor cells (4). By contrast, T cells expressing ␥␦ TCRs (5, 6) recognize antigens directly, with no requirement for antigen processing or presentation (7-9). Recently identified ligands for human ␥␦ T cells are MICA and MICB, which are distantly related to MHC class I but are functionally distinct. These molecules seem to have no role in the presentation of intracellular peptide antigens; instead, they may function as self-antigens that can be stress-induced (10). MICA and MICB are closely related and functionally indistinguishable (10-12). Both are recognized by cytotoxic ␥␦ T cells expressing the TCR variable region V ␦ 1. Although the recognition of MICA͞B appears to be mediated by TCR engagement, these interactions are unusual because T cells expressing diverse ␥ and ␦ chain V ␦ 1(D)J junctional sequences are capable of recognizing these molecules (10). This common antigen specificity may enable a subset of V ␦ 1 ␥␦ T cells, which are relatively infrequent and endowed with a limited TCR repertoire, to respond uniformly to expression of MICA͞B as a generic tissue distress signal that may be triggered by infection, noxious c...

SummaryAllergen specific CD4+ T cell clones generated from allergic individuals have been shown to produce increased levels of the cytokine interleukin 4 (IL-4), compared to allergen specific clones generated from nonallergic individuals. This difference between CD4+ T cells from allergic and nonallergic individuals with regard to cytokine production in response to allergen is thought to be responsible for the development of allergic disease with increased IgE synthesis in atopic individuals. We examined the production ofIL-4 in subjects with allergic rhinitis and in allergic individuals treated with allergen immunotherapy, a treatment which involves the subcutaneous administration of increasing doses of allergen and which is highly effective and beneficial for individuals with severe allergic rhinitis. We demonstrated that the quantity of IL-4 produced by allergen specific memory CD4+ T cells from allergic individuals could be considerably reduced by in vivo treatment with allergen (allergen immunotherapy) . Immunotherapy reduced IL-4 production by allergen specific CD4+ T cells to levels observed with T cells from nonallergic subjects, or to levels induced with nonallergic antigens such as tetanus toxoid . In most cases the levels of IL-4 produced were inversely related to the length of time on immunotherapy. These observations indicate that immunotherapy accomplishes its clinical effects by reducing IL-4 synthesis in allergen specific CD4+ T cells . In addition, these observations indicate that the cytokine profiles of memory CD4+ T cells can indeed be altered by in vivo therapies . Thus, the cytokine profiles of memory CD4+ T cells are mutable, and are not fixed as had been suggested by studies of murine CD4+ memory T cells. Finally, treatment of allergic diseases with allergen immunotherapy may be a model for other diseases which may require therapies that alter inappropriate cytokine profiles of memory CD4+ T cells .

SummaryWe have previously shown that CD4+ T cells from allergic individuals are predisposed to produce interleukin (IL)-4 in response to allergens, and that allergen immunotherapy greatly reduced Ib4 production in an allergen-specific fashion. The mechanism that results in the reduction of Ib4 synthesis in treated individuals is unknown, but because clinical improvement during immunotherapy is associated with the administration of the highest doses of allergen, we hypothesized that high concentration of allergen results in the downregulation of IL-4 synthesis in CD4 + T cells. In this report, we demonstrated that CD4+ T cells from allergic donors produced high levels of IL4 when stimulated with low concentrations of allergen (0.003-0.01/~g/ml), particularly when B cell-enriched populations presented the antigen. In contrast, the same responding CD4 + T ceU population produced little IL-4 when stimulated with high concentrations of allergen (10-30/~g/ml), especially when monocytes were used as antigen-presenting calls (APC). The quantity of Ib4 produced was also found to be inversely related to the extent of proliferation of the CD4+ T ceUs in response to allergen/antigen; maximal proliferation of CD4+ T cells occurred in response to high concentrations of antigen when II:4 production was minimal. Antigen presentation by B cell-enriched populations, instead of monocytes, induced less CD4 + T cell proliferation, but induced much greater Ib4 synthesis. Moreover, the addition of increasing numbers of APC (either B cells or monocytes) to cultures containing a constant number of responder T cells resulted in increased T cell proliferation and decreased Ib4 production. These results indicate that the circumstances under which memory T cells are activated, as well as the strength of the proliferative signal to T cells, greatly affect the quantity of Ib4 produced. Thus, our observations that the cytokine profile of allergen-specific memory CD4+ T cells can indeed be modulated by the antigen dose and APC type suggest that methods that preferentially enhance allergen uptake by monocytes and that enhance T cell proliferation will improve the clinical efficacy of immunotherapy in the treatment of allergic disease.

Alveolar macrophages, resident phagocytic cells in the lung that derive from peripheral blood monocytes, are paradoxically ineffective in presenting antigen to T cells. We found that antigen presentation by alveolar macrophages could be restored by the addition of anti-CD28 mAb to cultures of T cells and macrophages, indicating that costimulation by alveolar macrophages via the CD28 pathway was defective. In addition, we found that alveolar macrophages activated with IFN-y failed to express B7-1 or B7-2 antigens, which normally ligate CD28 on T cells and provide a costimulatory signal required for the activation of T cells. These observations are the first to demonstrate the inability of a "professional" antigen-presenting cell type to effectively express the costimulatory molecules B7-1 and B7-2. Inasmuch as immune reactions within the lung are inevitably associated with inflammatory injury to pulmonary tissue, these observations suggest that reduced expression of B7-1 and B7-2 by alveolar macrophages may be advantageous, as a critical mechanism involved in the induction of peripheral tolerance to the abundance of antigens to which mucosal tissues are continuously exposed. (J. Clin. Invest. 1995Invest. . 95:1415Invest. -1421

Despite accumulating data implicating Propionibacterium acnes in a variety of diseases, its precise role in infection remains to be determined. P. acnes antigen-specific CD4 + T cells are present in early inflamed acne lesions and may be involved in the inflammatory response; however, little is known about the specific antigens involved. In this study, B cell and T cell antigens from P. acnes expression libraries were cloned and evaluated and the four predominant proteins identified were investigated. Two of these antigens share some homology with an M-like protein of Streptococcus equi and have dermatan-sulphate-binding activity (PA-25957 and 5541). The remaining two antigens, PA-21693 and 4687, are similar to the product of the Corynebacterium diphtheriae htaA gene from the hmu ABC transport locus, although only one of these (PA-21693) is encoded within an hmu-like operon and conserved amongst a range of clinical isolates. All four proteins contain an LPXTG motif, although only PA-21693 contains a characteristic sortase-sorting signal. Variation in the expression of PA-4687, 25957 and 5541 is evident amongst clinical isolates and is generated both by frameshifts associated with the putative signal peptide and by variable numbers of repeat regions toward the carboxy-terminus, potentially generating heterogeneity of molecular mass and antigenic variation. In addition, in the case of PA-25957, a frameshift in a C-rich region at the extreme carboxy-terminus eliminates the LPXTG motif in some isolates. For the dermatan-sulphate-binding PA-25957, IgG1 antibody in serum from acne-positive donors was shown to be specific for the amino-terminal region of the protein, which also contains a CD4 + T cell epitope. In contrast, serum from acne-negative donors shows an IgG2 and IgG3 antibody subclass response to the carboxy-terminal region. These data have implications for the potential role of P. acnes in inflammatory acne and other diseases.