The Journal of Immunology, 2007,
179,
4951
-4952
Copyright © 2007 by The American Association of Immunologists, Inc.
IN THIS ISSUE
APCs in Diabetes
To assess the relative in vivo importance of different types of APCs in diabetes pathogenesis, Saxena et al. (p. 5041
) developed transgenic NOD mice in which treatment with diphtheria toxin led to the specific ablation of either macrophages or dendritic cells (DCs). Depletion of macrophages affected the development of neither spontaneous nor adoptively transferred diabetes. In contrast, mice depleted of DCs failed to develop diabetes, and restoration of myeloid DCs but not plasmacytoid DCs (pDCs) restored both effective Ag presentation to CD4+ T cells and diabetes progression. Interestingly, depletion of DCs after the onset of insulitis significantly accelerated progression to diabetes, suggesting that some DCs might act to inhibit diabetes pathogenesis. Indeed, restoration of pDCs slowed diabetes progression and was associated with a repopulation of the pancreas with both pDCs and NKT cells. The authors suggest that IDO production by pDCs may at least partially mediate diabetes inhibition. This study enhances our understanding of the roles of APC subsets in diabetes pathogenesis.
T Cell Manufacturing
An important goal in the development of adoptive T cell therapy is the effective in vitro generation of large numbers of fully functional human T cells of defined Ag specificity. Van Lent et al. (p. 4959
) developed an in vitro culture system in which human stem cells were retrovirally transduced with TCR genes and then induced to develop into T cells through coculture with OP9 stromal cells expressing the Notch ligand, Delta-like 1. During development, effective 
-chain allelic exclusion occurred, and CD8+ T cells matured and quickly expanded. These in vitro differentiated T cells were capable of Ag-specific proliferation and effective cytotoxic activity. Such Ag-specific, fully functional T cells were generated from cultures using hemopoietic stem cells obtained from postnatal thymus as well as, more importantly, stem cells collected noninvasively from umbilical cord blood. This work has important implications for both our understanding of human T cell development and future applications to antiviral and antitumor therapies.
Surviving T Cell Depletion
T cell depletion therapies can enhance transplantation tolerance but may leave populations of alloreactive T cells behind. Kroemer et al. (p. 5584
) examined anti-lymphocyte serum (ALS) depletion-resistant CD4+ T cells and found that they consistently expressed the costimulatory molecule OX40. This surviving cell population was heterogeneous, containing both Foxp3– effector T cells and Foxp3+ regulatory T cells (Tregs), and both subsets were functionally competent in inducing or preventing skin allograft rejection, respectively. Very few T cells survived depletion in the absence of OX40, whereas most CD4+ T cells survived depletion in mice overexpressing OX40L, indicating that the OX40/OX40L pathway is critical for cell survival in the context of ALS-mediated depletion. Interestingly, OX40 demonstrated opposing functions on depletion-resistant effector vs regulatory T cells, enhancing proliferation of effector cells while impairing the suppressor functions of Tregs. An understanding of the cells resistant to therapeutic T cell depletion may be important for the future development of strategies to enhance transplantation tolerance.
Cytotoxic T Cells in MS
Although CD8+ T cells have been proposed to play a major role in the pathogenesis of multiple sclerosis (MS), this possibility is poorly understood. To begin to characterize the role of CD8+ T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, Mars et al. (p. 5090
) sought to determine the fine specificity of the anti-myelin oligodendrocyte glycoprotein (MOG) CD8+ T cell response. Five candidate MOG epitopes that bound stably to HLA-A*0201 were identified, and all five were found to be highly immunogenic in HLA-A*0201 humanized transgenic mice. Four of these five peptides could be naturally processed from whole MOG, and two were identified as immunodominant. Immunization with one of these immunodominant peptides, MOG181, elicited a specific cytotoxic T cell response, leading the authors to assess this response’s encephalitogenic potential. Coadministration of MOG181 with a suboptimal dose of the well-defined encephalitogenic peptide MOG35–55 strongly exacerbated EAE development and severity. By identifying MHC class I-restricted MOG epitopes and demonstrating the encephalitogenicity of the T cell responses they induce, this work advances the understanding of the role of CD8+ T cells in the effector phase of EAE and, possibly, MS.
B Cells as APCs in Arthritis
The therapeutic efficacy of B cell depletion has indicated that B cells play a pathogenic role in rheumatoid arthritis. To determine whether these cells serve as APCs for autoreactive T cells, O’Neill et al. (p. 5109
) developed mice in which the costimulatory molecules CD80 and CD86 were absent on B cells but present on other APCs. Irradiated wild-type mice were reconstituted with a mix of bone marrow from B cell-deficient and CD80/86-deficient mice, resulting in mice with CD80/86+/+ non-B cells but with all B cells derived from the CD80/86–/– population. These bone marrow chimeras were completely resistant to proteoglycan (PG)-induced arthritis, similarly to mice entirely lacking CD80/86. However, these mice did not differ from wild-type mice in their production of pathogenic Abs, indicating that B cell-expressed CD80/86 is not required for the arthritic humoral response. T cells from these mice had a decreased ability to adoptively transfer arthritis, and their B cells inadequately stimulated T cell recall responses to PG, further emphasizing the importance of CD80/86 expression on B cells for the successful activation of T cells in arthritis.
Kinetics of T Cell Responses to HY
The kinetics of T cell responses to pathogens have been extensively studied; however, T cell responses to noninflammatory Ags are less well characterized. Tyznik and Bevan (p. 4988
) immunized female mice with male splenocytes and analyzed the kinetics of CD4+ and CD8+ T cell responses to male-specific minor histocompatibility HY Ags. In this system, the CD8+ T cell response was unexpectedly delayed by several days as compared with pathogen-induced CTL responses, whereas the CD4+ T cell response required to provide help to the CD8+ T cells developed without delay. These CD4+ T cells recognized Ag presented by host rather than donor APCs and were able to directly lyse male cells in vivo. However, a CTL response was necessary to clear the male cells, and it was found that the delay in CTL activation was caused by donor CD8+ T cells acting as "veto cells" in a dose-dependent manner. The qualitative differences observed between these responses to antigenic cells and those observed in inflammatory conditions provide a novel picture of the interactions between CD4+ and CD8+ T cells in vivo.
IVIg Stimulates Tregs
Intravenous Ig (IVIg) administration has been found to be effective in the treatment of autoimmune disease, but its modes of action are not fully elucidated. The wide variety of mechanisms attributed to IVIg to date include inhibitory binding to autoantibodies, Fc receptors, BAFF, and complement; the induction of apoptosis in lymphocytes and monocytes, and the inhibition of dendritic cell differentiation. Kessel et al. (p. 5571
) wondered whether, in addition to these reported activities, IVIg might also enhance the activity of regulatory T cells (Tregs). Indeed, when Tregs were cultured with IVIg, the authors observed significant up-regulation of Foxp3, IL-10, and TGF- mRNA expression. In addition, IVIg enhanced the ability of Tregs to suppress effector CD4+ T cell activity, as measured by the inhibition of TNF-
production in a coculture system. As functional defects in regulatory T cells have been observed in multiple autoimmune diseases, these data may help explain a mechanism of IVIg benefit in the treatment of certain autoimmune diseases.
Survival via PDL1
Successful transplantation tolerance requires extensive regulation of alloreactive T cells. Tanaka et al. (p. 5204
) analyzed the role of the PD-1:PDL costimulatory pathway in the induction and maintenance of transplantation tolerance in a mouse model of CTLA4-Ig therapy and found that this pathway was important in acquired but not central tolerance. Blockade of PDL1 but not PDL2 abrogated CTLA4-Ig-induced tolerance of cardiac allografts whether administered before or well after transplantation. Anti-PDL1 treatment increased the frequency of effector CD8+ T, Th1, and Th2 cells and decreased the frequency of graft-infiltrating regulatory T cells compared with the frequencies observed in mice receiving CTLA4-Ig treatment alone. In support of these findings, PDL1-deficient mice undergoing CTLA4-Ig therapy showed significantly increased graft rejection compared with wild-type recipients, whereas PDL2-deficient mice accepted grafts similarly as wild-type mice. Interestingly, PDL1-deficient grafts were initially accepted by wild-type mice treated with CTLA4-Ig but over time showed severe chronic rejection. Recognition of the importance of the PD-1:PDL1 interaction in transplantation tolerance may lead to the development of therapeutic strategies to enhance graft acceptance.
Summaries written by Jennifer Hartt Meyers, Ph.D.
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