The Therapeutic Potential of T Cell Metabolism.

Transplant rejection mediated by the adaptive immune system remains a major barrier to achieving long-term tolerance and graft survival. Emerging evidence indicates that lymphocytes rapidly shift their metabolic programs in response to activation, co-stimulatory, and cytokine signals to support required effector cell differentiation and function. These observations have led to the hypothesis that manipulating the metabolic programs of immune cells could serve as a powerful therapeutic strategy for attenuating deleterious immune responses and facilitating durable tolerance in the setting of allogeneic solid organ or bone marrow transplant. In this mini-review, we introduce the fundamentals of metabolism, highlight the current understanding of how adaptive immune cells utilize their metabolic programs, and discuss the potential for targeting metabolism as a therapeutic approach to induce tolerance in the transplant setting.

Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells.

CD4(+)25(+) T cells are a unique population of immunoregulatory T cells which are critical for the prevention of autoimmunity. To address the thymic selection of these cells we have used two models of attenuated thymic deletion. In K14-A(beta)(b) mice, major histocompatibility complex (MHC) class II I-A(b) expression is limited to thymic cortical epithelium and deletion by hematopoietic antigen-presenting cells does not occur. In H2-DMalpha-deficient mice, MHC class II molecules contain a limited array of self-peptides resulting in inefficient clonal deletion. We find that CD4(+)25(+) T cells are present in the thymus and periphery of K14-A(beta)(b) and H2-DMalpha-deficient mice and, like their wild-type counterparts, suppress the proliferation of cocultured CD4(+)25(-) effector T cells. In contrast, CD4(+)25(+) T cells from MHC class II-deficient mice do not suppress responder CD4(+) T cells in vitro or in vivo. Thus, development of regulatory CD4(+)25(+) T cells is dependent on MHC class II-positive thymic cortical epithelium. Furthermore, analysis of the specificities of CD4(+)25(+) T cells in K14-A(beta)(b) and H2-DMalpha-deficient mice suggests that a subset of CD4(+)25(+) T cells is subject to negative selection on hematopoietic antigen-presenting cells.

High RAD51 mRNA levels in young rabbit appendix. A role in B-cell gene conversion?

The rabbit has a limited number of VH genes that rearrange. As in the chicken, the 3'-most VH1 gene is rearranged in most B lymphocytes. This laboratory reported that by 6 weeks after birth, diversification of rearranged VH genes occurs, at least in part, by gene conversion-like events in the appendix, suggesting that this organ is a homologue of the avian bursa of Fabricius. Rad51 contributes to the repair of double-strand breaks in DNA during somatic and meiotic recombination. The gene was first identified in lower eukaryotes, and later in vertebrates including chicken, as encoding an Escherichia coli RecA-like protein. We report the cloning and sequencing of RAD51 from the rabbit. Because the chicken bursa was shown to express high levels of RAD51 message, we investigated the expression of RAD51 in the rabbit appendix and other tissues. Using a quantitative polymerase chain reaction mimic assay and conventional northern analyses, we found high RAD51 expression in young rabbit appendix comparable to levels in testis where there is an abundance of meiotic recombination. RAD51 levels were three times higher in appendix B lymphocytes compared with T lymphocytes and were lower in adult appendix, as well as in spleen and Peyer's patches of young rabbits. We measured the levels of message in several appendix cell sub-populations obtained by fluorescence-activated cell sorting and found that sub-populations of B lymphocytes corresponding to different stages of B-cell development as well as B cells undergoing isotype switch did not have significantly different mRNA levels.

Leishmania spp: temperature sensitivity of promastigotes in vitro as a model for tropism in vivo.

Since in humans, skin temperature is lower than internal temperature, the temperature sensitivity of Leishmania may influence the tropism of Leishmania in the human host; temperature-sensitive parasites may remain in the skin, temperature-resistant parasites may go to the viscera. In order to pursue the genetic factors controlling Leishmania tropism, we have developed an in vitro promastigote temperature model. Promastigote growth is measured at 30, 32, and 34 degrees C and compared with growth at the control temperature (25 degrees C). The results from tests of the promastigote temperature sensitivity of eight species (33 different strains) show that visceral species (L. donovani and L. chagasi) are more temperature resistant than cutaneous species (L. major, L. tropica, L. mexicana, L. braziliensis, L. panamensis, and L. amazonensis), that Old World species are more temperature-resistant than New World species, and that within the New World cutaneous species there are three distinct temperature sensitivity groupings (L. mexicana > L. braziliensis and L. panamensis > L. amazonensis). Interestingly, viscerotropic L. tropica from Operation Desert Storm and L. donovani complex strains isolated from cutaneous lesions are more and less temperature-sensitive, respectively, than strains of the same species with the expected tropism in vivo.