This result suggests that decreased production of IFN- could be rescued by manipulation of CD244/2B4 receptor signaling

This result suggests that decreased production of IFN- could be rescued by manipulation of CD244/2B4 receptor signaling. Open in a separate window Figure 5 Rescue of IFN- production following CD244/2B4 receptor blocking.(A) Representative flow cytometric plots showing IFN- production in stimulated CD3+CD4+ T cells when incubated with isotype control antibody (ISO) or blocking anti-CD244/2B4 antibody clone eBioPP35 (BL). In conclusion, CD244/2B4 signaling pathway has an inhibitory role on antigen-specific CD4+ T cell function. Introduction Tuberculosis (TB) is the second leading cause of death from an infectious disease worldwide [1]. It is estimated that 8.8 million cases of TB occurred in 2010 2010 and 2.6 million were smear-positive. In 2010 2010 alone, there were estimated 1.1 million deaths from TB in HIV-negative people and 0.35 million deaths from HIV-associated TB [1]. Despite high rate of contamination in humans, especially in developing countries, only 5C10% of infected people develop into active TB in their life time [2], [3], [4]. The observation suggests that development into active TB is largely determined by immune responses of the host. Previous studies have proved the crucial role of CD4+ T cells in protective immunity against contamination, while other cells, such as CD8+ T cells, T cells and CD1-restricted T cells also play important functions [2], [5], [6], [7], [8], [9], [10]. CD4 knockout mice exhibited increased susceptibility to contamination, compared with wild-type mice [5]. AIDS patients have severe defects in CD4+ T cells and are highly susceptible to development of active TB [1], [6]. T cell immune responses are regulated by different activating and inhibitory surface receptors. contamination promotes up-regulation of inhibitory receptor PD-1, its ligands, PD-L1 and PD-L2, on T cells from patients with active TB. Blockage of PD-1 or PD-1 and Rabbit Polyclonal to AOX1 its ligands leads to significantly improved IFN- production and degranulation of T cells [11]. PD-1?/? mice have excessive inflammatory responses after contamination [12]. The T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3), an inhibitory receptor highly expressed on exhausting T cells [13], is usually up-regulated on both total CD8 and antigen-specific CD8 T cells from active TB patients [14]. The elevated expression of Tim-3 on CD8 T cells is usually significantly associated with T cell dysfunctions and disease severity of TB patients. Blocking of Tim-3 signaling led to significantly increased production of IFN- [14]. These studies indicate that this PD-1 and Tim-3 signaling pathways inhibit T cell effector functions during contamination. It would be interesting Cidofovir (Vistide) to investigate whether other costimulatory Cidofovir (Vistide) receptors are involved in the regulation of anti-TB immunity. CD244 (also called 2B4) is a Cidofovir (Vistide) member of the signaling lymphocyte activation molecule (SLAM) family of immune cell receptors [15], [16], [17]. It is expressed on natural killer (NK) cells, CD4 and CD8 T cells, T cells, monocytes, eosinophils and basophiles [18]. The function of CD244/2B4 on NK cells has been studied extensively; it was initially described as an activating receptor and was later found to have both activating and inhibitory functions in mouse NK cells [15], [16], [19], [20], [21]. The phosphorylated ITSMs of CD244/2B4 tail can bind to signaling lymphocyte activation moleculeCassociated protein (SAP), and it also can recruit phosphatases such as SHP-1, SHP-2, SHIP, and the inhibitory kinase Csk [21]. It is found that 2B4 exhibited an activating function when expressed at low levels, while generated an inhibitory signal when expressed at high levels [22]. Previously studies have found that CD244/2B4 plays an important role in modulating CD8+ T cell immunity during contamination [23], [24], [25], [26], [27]. To our knowledge, the role of CD244/2B4 on human CD4+ T cell function in TB patients has not been reported so far. CD4 T cells play a central role in human immune protection and its importance is clearly demonstrated in AIDS patients. Depletion in CD4 T cells leads.