Anjana Ray

The contrasting role of B7-H3

Tlymphocytes of adaptive immunity provide vertebrates with the ability to survey for and respond specifically to an incredible diversity of antigens, whether foreign or native. Appropriate T cell response is required to eradicate pathogens, whereas abnormal T cell function could lead to autoimmune diseases, cancer, and transplantation rejection. The outcome of T cell engagement of antigen is determined by positive costimulation and negative coinhibition; both are primarily generated by the interaction between the B7 family and their receptor CD28 family (1). Recent years have seen the identification of several new members of B7/CD28 families. The growing B7 family now comprises seven members: B7-1 (CD80), B7-2 (CD86), B7h (CD275), PD-L1 (CD274), PD-L2 (CD273), B7-H3 (CD276), and B7x (B7-H4 or B7S1). Almost 5 years ago, we divided the B7 family into three groups by phylogenetic analysis: group I includes B7-1, B7-2, and B7h; group II consists of PD-L1 and PD-L2; and group III contains B7x and B7-H3 (2, 3). Receptors for group I are CD28, CTLA-4, and ICOS, and the receptor for group II is PD-1 (Fig. 1). B7-1 also binds PD-L1. One prediction of the phylogenetic comparison was that receptor(s) for B7-H3 would not be real homologue(s) of receptors for group I and II (3). Five years later, this prediction has been proven true (3). In this issue of PNAS, Hasiguchi et al. (3, 4) have identified one such receptor, triggering receptor expressed on myeloid cell (TREM)-like transcript 2 (TLT-2, or TREML2), which binds B7-H3 and costimulates activation of CD8 T cells in particular. TLT-2 is a member of the TREM receptor family (5, 6), which includes TREM-1, -2, and -3, as well as TLT-1 and -2. B7-H3 is the first ligand to be identified for the TREM … ¶To whom correspondence should be addressed. E-mail: xzang{at}aecom.yu.edu

Antimicrobial photodynamic therapy: an effective alternative approach to control fungal infections

Skin mycoses are caused mainly by dermatophytes, which are fungal species that primarily infect areas rich in keratin such as hair, nails, and skin. Significantly, there are increasing rates of antimicrobial resistance among dermatophytes, especially for Trichophyton rubrum, the most frequent etiologic agent worldwide. Hence, investigators have been developing new therapeutic approaches, including photodynamic treatment. Photodynamic therapy (PDT) utilizes a photosensitive substance activated by a light source of a specific wavelength. The photoactivation induces cascades of photochemicals and photobiological events that cause irreversible changes in the exposed cells. Although photodynamic approaches are well established experimentally for the treatment of certain cutaneous infections, there is limited information about its mechanism of action for specific pathogens as well as the risks to healthy tissues. In this work, we have conducted a comprehensive review of the current knowledge of PDT as it specifically applies to fungal diseases. The data to date suggests that photodynamic treatment approaches hold great promise for combating certain fungal pathogens, particularly dermatophytes.

Host B7x Promotes Pulmonary Metastasis of Breast Cancer

B7x (B7-H4 or B7S1) is an inhibitory member of the B7 family of T cell costimulation. It is expressed in low levels in healthy peripheral tissues, such as the lung epithelium, but is overexpressed in a variety of human cancers with negative clinical associations, including metastasis. However, the function of B7x in the context of cancer, whether expressed on cancer cells or on surrounding “host” tissues, has not been elucidated in vivo. We used the 4T1 metastatic breast cancer model and B7x knockout (B7x −/−) mice to investigate the effect of host tissue–expressed B7x on cancer. We found that 4T1 cells were B7x negative in vitro and in vivo, and B7x−/− mice had significantly fewer lung 4T1 tumor nodules than did wild-type mice. Furthermore, B7x−/− mice showed significantly enhanced survival and a memory response to tumor rechallenge. Mechanistic studies revealed that the presence of B7x correlated with reduced general and tumor-specific T cell cytokine responses, as well as with an increased infiltration of immunosuppressive cells, including tumor-associated neutrophils, macrophages, and regulatory T cells, into tumor-bearing lungs. Importantly, tumor-associated neutrophils strongly bound B7x protein and inhibited the proliferation of both CD4 and CD8 T cells. These results suggest that host B7x may enable metastasizing cancer cells to escape local antitumor immune responses through interactions with the innate and adaptive immune systems. Thus, targeting the B7x pathway holds much promise for improving the efficacy of immunotherapy for metastatic cancer.

HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function

T-cell costimulation and coinhibition generated by engagement of the B7 family and their receptor CD28 family are of central importance in regulating the T-cell response, making these pathways very attractive therapeutic targets. Here we describe HERV–H LTR-associating protein 2 (HHLA2) as a member of the B7 family that shares 10–18% amino acid identity and 23–33% similarity to other human B7 proteins and phylogenetically forms a subfamily with B7x and B7-H3 within the family. HHLA2 is expressed in humans but not in mice, which is unique within the B7 and CD28 families. HHLA2 protein is constitutively expressed on the surface of human monocytes and is induced on B cells after stimulation with LPS and IFN-γ. HHLA2 does not interact with other known members of the CD28 family or the B7 family, but does bind a putative receptor that is constitutively expressed not only on resting and activated CD4 and CD8 T cells but also on antigen-presenting cells. HHLA2 inhibits proliferation of both CD4 and CD8 T cells in the presence of T-cell receptor signaling. In addition, HHLA2 significantly reduces cytokine production by T cells including IFN-γ, TNF-α, IL-5, IL-10, IL-13, IL-17A, and IL-22. Thus, we have identified a unique B7 pathway that is able to inhibit human CD4 and CD8 T-cell proliferation and cytokine production. This unique human T-cell coinhibitory pathway may afford unique strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection and may help to design better vaccines.

B7x in the Periphery Abrogates Pancreas-Specific Damage Mediated by Self-reactive CD8 T Cells

B7x (B7-H4 or B7S1) is the seventh member of the B7 family, and its in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. In this study, we showed that B7x protein was not detected on APCs or T cells in both human and mice, which is unique in the B7 family. Because B7x protein is expressed in some peripheral cells such as pancreatic β cells, we used a CD8 T cell-mediated diabetes model (AI4αβ) in which CD8 T cells recognize an endogenous self-Ag, and found that mice lacking B7x developed more severe diabetes than control AI4αβ mice. Conversely, mice overexpressing B7x in the β cells (Rip-B7xAI4αβ) were diabetes free. Furthermore, adoptive transfer of effector AI4αβ CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4αβ mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4αβ mice. Although AI4αβ CD8 T cells in Rip-B7xAI4αβ and AI4αβ mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4αβ mice than in RIP-B7xAI4αβ mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells, and that local overexpression of B7x on pancreatic β cells is sufficient to abolish CD8 T cell-induced diabetes.