Functional defects in cytotoxic CD8؉ T cell responses arise in chronic human viral infections, but the mechanisms involved are not well understood. In mice, CD4 cell-mediated interleukin-21 (IL-21) production is necessary for the maintenance of CD8 ؉ T cell function and control of persistent viral infections. To investigate the potential role of IL-21 in a chronic human viral infection, we studied the rare subset of HIV-1 controllers, who are able to spontaneously control HIV-1 replication without treatment. HIV-specific triggering of IL-21 by CD4؉ T cells was significantly enriched in these persons (P ‫؍‬ 0.0007), while isolated loss of IL-21-secreting CD4 ؉ T cells was characteristic for subjects with persistent viremia and progressive disease. IL-21 responses were mediated by recognition of discrete epitopes largely in the Gag protein, and expansion of IL-21 cells in acute infection resulted in lower viral set points (P ‫؍‬ 0.002). Moreover, IL-21 production by CD4؉ T cells of HIV controllers enhanced perforin production by HIV-1-specific CD8 ؉ T cells from chronic progressors even in late stages of disease, and HIV-1-specific effector CD8؉ T cells showed an enhanced ability to efficiently inhibit viral replication in vitro after IL-21 binding. These data suggest that HIV-1-specific IL-21؉ CD4 ؉ T cell responses might contribute to the control of viral replication in humans and are likely to be of great importance for vaccine design. CD4ϩ T cell help is essential to generate long-lived antiviral CD8 ϩ T cell memory (17, 18). Although antigen-specific CD8 ϩ T cells can be primed in the absence of CD4 ϩ T cell help, secondary expansion upon antigen reencounter is inefficient under such circumstances (7,11,18,22). Progressive loss of CD4 ϩ T cells in human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections has been associated with dysfunction of virus-specific CD8 ϩ T cells and ineffective containment of these chronic viral infections. Moreover, under repetitive antigenic stimulation, virus-specific cytotoxic CD8 ϩ T cells (CTL) become increasingly impaired, exhibiting decreased effector functions and upregulation of negative immunoregulatory molecules (2, 19). This dysfunction is likewise more severe in the absence of CD4 ϩ T cell help (21). The nature of CD4 help required to control chronic human infections remains unclear. In mice, recent studies indicate that CD4 ϩ T cell production of interleukin-21 (IL-21), a common ␥-chain cytokine, is required for maintenance of CD8 ϩ T cell function in persistent but not resolving viral infections (3,4,23). During lymphocytic choriomeningitis virus (LCMV) infection, expansion of CD4 ϩ T helper cells producing IL-21 is required for sustained CD8 ϩ T cell proliferation and control of viremia. In contrast, mice lacking either IL-21 or the IL-21 receptor are more susceptible to uncontrolled chronic LCMV infection, providing evidence that this cytokine is a key regulator of viral control in a murine model of chronic viral infection.

Regulatory T cells (Tregs) are potent immune modulators, but their role in human immunodeficiency virus type 1 (HIV-1) pathogenesis remains poorly understood. We performed a detailed analysis of the frequency and function of Tregs in a large cohort of HIV-1-infected individuals and HIV-1 negative controls. While HIV "elite controllers" and uninfected individuals had similar Treg numbers and frequencies, the absolute numbers of Tregs declined in blood and gut-associated lymphoid tissue in patients with chronic progressive HIV-1 infection. Despite quantitative changes in Tregs, HIV-1 infection was not associated with an impairment of ex vivo suppressive function of flow-sorted Tregs in both HIV controllers and untreated chronic progressors.

Under persistent antigenic stimulation, virus-specific CD8 ؉ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1). Here, we demonstrate that HIV-1 antigen-specific T cells from subjects with chronicprogressive HIV-1 infection have significantly elevated KLRG1 expression (P < .001); show abnormal distribution of E-cadherin, the natural ligand of KLRG1, in the intestinal mucosa; and have elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HIV-1 viral load (R ‫؍‬ 0.7, P ‫؍‬ .004). We furthermore demonstrate that in the presence of sE-cadherin, KLRG1 hi HIV-1-specific CD8 ؉ T cells are impaired in their ability to respond by cytokine secretion on antigenic stimulation (P ‫؍‬ .002) and to inhibit viral replication (P ‫؍‬ .03) in vitro. Thus, these data suggest a critical mechanism by which the disruption of the intestinal epithelium associated with HIV-1 leads to increased systemic levels of sE-cadherin, which inhibits the effector functions of KLRG1 hiexpressing HIV-1-specific CD8 ؉ T cells systemically.(Blood. 2011;117(19): 5112-5122) IntroductionCytolytic CD8 ϩ T-cell responses have been shown to play a major role in the pathogenesis of viral infections. After acute viral infection, virus-specific CD8 ϩ T cells undergo sequential activation and expansion, and in the process they acquire effector functions such as the production of the antiviral cytokines IFN-␥ and TNF-␣. 1 However, during persistent viral infections the function and differentiation of virus-specific CD8 ϩ T cells become progressively "exhausted" as a consequence of persistent viremia. [2][3][4] Several molecules have been identified as important mediators of T-cell exhaustion, including programmed death-1 (PD-1), 3,5 CTLA-4, 4 and Lag3. 6 It is thought that each of these molecules serves to regulate the function of antigen-specific CD8 ϩ T cells, yet the measure of regulation and interdependence of each of these pathways is unknown.The killer cell lectin-like receptor G1 (KLRG1) plays a unique but poorly characterized role in mediating T-cell exhaustion. KLRG1 is expressed on a subset of CD4 ϩ , CD8 ϩ T cells, as well as on natural killer cells. [7][8][9] On CD8 ϩ T cells, KLRG1 is upregulated on virus-specific T cells in response to repetitive antigenic stimulation. Indeed, most virus-specific CD8 ϩ T cells are KLRG1 ϩ in chronic viral infections such as CMV and EBV, but not in cleared infections such as influenza. [10][11][12] However, the role of KLRG1 in HIV-1 infection remains largely unknown. 12 The ligand for KLRG1 was identified as E-cadherin, a member of the cadherin (calcium-dependent adhesion molecules) family of type I transmembrane proteins that forms tight intracellular connections between cells within epithelial surfaces. [13][14][15] It is expressed at high levels within the gastrointestinal epithelium, and disruption of the integrity of mucosal membranes that occurs in the setting of invasive gastrointestinal...