During activation, T cells express receptors for receiving positive and negative costimulatory signals. Here we identify the B and T lymphocyte attenuator (BTLA), an immunoglobulin domain-containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (T(H)1) but not T(H)2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation, and BTLA-deficient mice have increased specific antibody responses and enhanced sensitivity to experimental autoimmune encephalomyelitis. B7x, a peripheral homolog of B7, is a ligand of BTLA. Thus, BTLA is a third inhibitory receptor on T lymphocytes with similarities to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1).

Evaluation of the pedal arteries has not been well evaluated by noninvasive duplex ultrasound. It offers an alternative approach that directly studies the angiosome supply of the foot. The goal of this article is to describe the technique, protocol, and criteria to properly evaluate the pedal arteries of the foot with noninvasive duplex ultrasound.

To address the issue of veteran-centered care education more broadly, the authors have developed a massive open online course for health professionals, using most of the content from this workshop, which will be offered in spring 2016. Another important next step will be to deliver this workshop to and collect evaluation data from non-VA providers.

T cells expressing high levels of inhibitory receptors such as PD-1 and LAG-3 are a hallmark of chronic infections and cancer. Checkpoint blockade therapies targeting these receptors have been largely validated as promising strategies to restore exhausted T cell functions and clearance of chronic infections and tumors. The inability to develop long-term natural immunity in malaria-infected patients has been proposed to be at least partially accounted for by sustained expression of high levels of inhibitory receptors on T and B lymphocytes. While blockade or lack of PD-1/PD-L1 and/or LAG-3 was reported to promote better clearance of Plasmodium parasites in various mouse models, how exactly blockade of these pathways contributes to enhanced protection is not known. Herein, using the mouse model of non-lethal P. yoelii (Py) infection, we reveal that the kinetics of blood parasitemia as well as CD4+ T follicular helper (TFH) and germinal center (GC) B cell responses are indistinguishable between PD-1-/-, PD-L1-/- and WT mice. Yet, we also report that monoclonal antibody (mAb) blockade of LAG-3 in PD-L1-/- mice promotes accelerated control of blood parasite growth and clearance, consistent with prior therapeutic blockade experiments. However, neither CD4+ TFH and GC B cell responses, nor parasite-specific Ab serum titers and capacity to transfer protection differed. We also found that i) the majority of LAG-3+ cells are T cells, ii) selective depletion of CD4+ but not CD8+ T cells prevents anti-LAG-3-mediated protection, and iii) production of effector cytokines by CD4+ T cells is increased in anti-LAG-3-treated versus control mice. Thus, taken together, these results are consistent with a model in which blockade and/or deficiency of PD-L1 and LAG-3 on parasite-specific CD4+ T cells unleashes their ability to effectively clear blood parasites, independently from humoral responses.

These authors contributed equally to this work. AbstractT cells expressing high levels of inhibitory receptors such as PD-1 and LAG-3 are a hallmark of chronic infections and cancer. Checkpoint blockade therapies targeting these receptors have been largely validated as promising strategies to restore exhausted T cell functions and clearance of chronic infections and tumors. The inability to develop long-term natural immunity in malariainfected patients has been proposed to be at least partially accounted for by sustained expression of high levels of inhibitory receptors on T and B lymphocytes. While blockade or lack of PD-1/PD-L1 and/or LAG-3 was reported to promote better clearance of Plasmodium parasites in mice, how exactly these pathways contributes to protection is not known. Herein, using a mouse model of non-lethal P. yoelii (Py) infection, we reveal that the kinetics of blood parasitemia is indistinguishable between PD-1 -/-, PD-L1 -/and WT mice. Yet, monoclonal antibody (mAb) blockade of LAG-3 in PD-L1 -/mice promoted accelerated control of blood parasite growth and clearance. We also report that i) the majority of LAG-3 + cells are T cells, ii) selective depletion of CD8 + T cells did not prevent anti-LAG-3-mediated protection, and iii) production of effector cytokines by CD4 + T cells is increased in anti-LAG-3-treated versus control mice. In addition, parasite-specific Ab serum titers and their ability to transfer protection from both groups of mice was comparable and depletion of CD4 + T cells prevented protection. Thus, taken together, these results are consistent with a model in which disruption of PD-L1 and LAG-3 on parasite-specific CD4 + T cells unleashes their ability to effectively clear blood parasites, independently from humoral responses. Author SummaryMalaria, caused by Plasmodium parasites, is a global burden for which an efficacious vaccine is urgently needed. The development of long-term immunity against malaria is unclear, but we know that both T and B (that produce antibodies, Ab) lymphocytes, that are subsets of white blood cells, are required. Studies in mouse models of malaria have suggested that sets of inhibitory receptors, namely LAG-3 and PD-1, expressed on cytotoxic and helper T lymphocytes hamper the development of effective immunity against malaria. Therapeutic blockade of these receptors was reported to enhance blood parasite clearance through the development of more protective parasitespecific helper T lymphocytes and Abs. Herein, we reveal that, while mice genetically deficient for the PD-1 pathway fail to clear blood parasites better than WT counterparts, anti-LAG-3 treatment does. Importantly, we found comparable parasite-specific Ab responses between all mouse groups, and Ab transfers conferred similar protection to newly infected mice. We also show that LAG-3 is mostly expressed on T lymphocytes, and that cytotoxic T lymphocytes are not involved in anti-LAG-3 accelerated clearance of parasites. Our results suggest that LAG-3 blockade acts on helper T lymphocytes to un...