Tumor-associated immune suppression can lead to defective T cell-mediated antitumor immunity. Here, we identified a unique phenotype of exhausted T cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the coexpression of Tim-3 and PD-1 on CD8 ؉ T cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 coexpression increased during AML progression. PD-1 ؉ Tim-3 ؉ CD8 ؉ T cells were deficient in their ability to produce IFN-␥, TNF-␣, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3 ؉ PD-1-KO CD8 ؉ T cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced T-regulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8 ؉ T cells. Whereas blocking the PD-1/ PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing-albeit not eliminating-both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8 ؉ T-cell exhaustion in patients with hematologic malignancies such as advanced AML. (Blood. 2011;117(17):4501-4510) Introduction T-cell exhaustion, a state of T-cell dysfunction characterized by diminished cytokine production, impaired killing, and hypoproliferation, was first characterized in the settings of chronic lymphocytic choriomeningitis virus (LCMV) infection. 1,2-5 Since its discovery, the process of T-cell exhaustion has been of intense interest and has been the subject of study in viral infections such as hepatitis C virus 2,6 and HIV, 3,7 as well as in tumor models. 8,9,10,11 Cell-surface antigen determinants such as program death-1 (PD-1), CTLA-4, and, in some instances, CD28 (eg, hepatitis C viral infection) can be used to identify antigen-specific T cells that are at an exhaustion stage. 4 T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) is a type I membrane glycoprotein and its expression can be found on terminally differentiated Th1 cells and innate immune cells. [12][13][14] is its only confirmed Tim-3 ligand to date, 15,16 although it is known that Tim-3 can also bind to certain carbohydrate moieties. 17 Ligation of Tim-3 on T cells and gal-9 inhibits Th1 responses and plays an important role in infection, autoimmunity, peripheral tolerance, and inflammation. 14,[18][19][20][21] In addition to its negative regulatory role in dampening the immune system, a recent report showed a synergistic effect of Tim-3 signaling and lipopolysaccharide in producing proinflammatory cytokines by naive dendritic cells (DCs) and monocytes, 22 indicating a dual role of the Tim-3 signaling pathway at a different phase of immune responses.Studies have demonstrated a strong correlation between PD-1 and Tim-3 coexpressi...

Myeloid-derived suppressor cells (MDSCs

Key Points• T follicular helper cells and germinal center B cells are increased and strongly correlate with the development of cGVHD in a murine model. • Blocking mAbs for IL-21, ICOS, and CD40L are potential novel therapeutics for cGVHD.Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD. (Blood. 2014;123(25):3988-3998)

Interleukin 7 (IL-7) and T cell receptor (TCR) signals have been proposed to be the primary drivers of homeostatic T cell proliferation. However, it is not known why CD4+ T cells undergo less efficient homeostatic proliferation than CD8+ T cells. Here we showed that systemic IL-7 concentrations rise during lymphopenia due to diminished IL-7 utilization, but that IL-7 signaling on IL-7Rα+ dendritic cells (DCs) in lymphopenic settings paradoxically diminishes CD4+ T cell homeostatic proliferation. This effect is mediated, at least in part, by IL-7-mediated downregulation of MHC class II expression on IL-7Rα+ DCs. These results implicate IL-7Rα+ DCs as regulators of the peripheral CD4+ T cell niche, and indicate that IL-7 signals in DCs prevent uncontrolled CD4+ T cell expansion in vivo.