T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged and T cell exhaustion has been defined in many experimental and clinical settings. Although the pathways involved remain to be fully defined, advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities.

T cell exhaustion

Redefining Chronic Viral Infection

In this Review, Nicole Baumgarth describes the development and functions of B-1 cells. These innate-like B cells serve as the major source of natural antibody in mice, and can have important roles in defence against mucosal pathogens and in maintaining tissue homeostasis. During their development, B and T cells with self-reactive antigen receptors are generally deleted from the repertoire to avoid autoimmune diseases. Paradoxically, innate-like B-1 cells in mice are positively selected for self-reactivity and form a pool of long-lived, self-renewing B cells that produce most of the circulating natural IgM antibodies. This Review provides an overview of the developmental processes that shape the B-1 cell pool in mice, outlines the functions of B-1 cells in both the steady state and during host defence, and discusses possible functional B-1 cell homologues that exist in humans.

The double life of a B-1 cell: self-reactivity selects for protective effector functions

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.

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Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

In recent years, intense research efforts have been dedicated to elucidating the pathogenic mechanisms of HIV-associated disease progression. In addition to the progressive depletion and dysfunction of CD4(+) T cells, HIV infection also leads to extensive defects in the humoral arm of the immune system. The lack of immune control of the virus in almost all infected individuals is a great impediment to the treatment of HIV-associated disease and to the development of a successful HIV vaccine. This Review focuses on advances in our understanding of the mechanisms of B-cell dysfunction in HIV-associated disease and discusses similarities with other diseases that are associated with B-cell dysfunction.

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B cells in HIV infection and disease

Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20hi/CD27lo/CD21lo) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20hi/CD27−/CD21lo) when compared with B cells with a classical memory (CD27+) or naive (CD27−/CD21hi) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.

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Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals

This study aimed to investigate the effects of compound non-starch polysaccharide (NSP) enzymes on growth performance, slaughter performance, immune function, and apparent utilization of nutrients in broiler chickens fed a low-metabolizable energy diet. A total of 240 healthy 1-day-old AA broilers (Arbor Acres, 47.2 ± 0.31 g) were randomly divided into four treatment groups, each with six replicate groups and 10 broilers per replicate. The control group was fed a basal diet; the EL-H group was fed the basal diet supplemented with 200 mg/kg compound NSP enzyme, including β-mannanase 5,000 IU/g, β-glucanase 2000 IU/g, xylanase 10,000 IU/g, and cellulase 500 IU/g. The EL-M group was fed the basal diet with 50 kcal/kg metabolizable energy removed, supplemented with 200 mg/kg compound NSP enzyme. Finally, the EL-L group was fed the basal diet with 100 kcal/kg metabolizable energy removed, supplemented with 200 mg/kg compound NSP enzyme. The results showed that feeding with a low-metabolizable energy diet supplemented with compound NSP enzymes did not significantly affect the growth performance of broilers (p > 0.05). Compared with the control group, the abdominal fat rate of broilers in the EL-L group was significantly reduced, and that of broilers in the EL-M group was significantly increased (p < 0.05). Apparent utilization of dry matter, crude protein, and energy in the diet was lower in the control group than in the EL-L group, but significantly higher in the control group than in the EL-H group (p < 0.05). In addition, apparent utilization of crude fiber was significantly increased in the EL-H, EL-M, and EL-L groups compared with the control group (p < 0.05). In conclusion, this experiment showed that the addition of 200 mg/kg compound NSP enzyme enabled maintenance of the normal growth and development of broiler chickens fed a low-metabolizable energy diet (replacing 50–100 kcal/kg metabolizable energy). This study provides a theoretical basis for the application of the compound NSP enzyme in broiler chickens.

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Compound non-starch polysaccharide enzymes improve growth performance, slaughter performance, immune function, and apparent utilization rate of nutrients in broiler chickens fed a low-metabolizable energy diet

Wei-wei Wang

Papers

Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals

Compound non-starch polysaccharide enzymes improve growth performance, slaughter performance, immune function, and apparent utilization rate of nutrients in broiler chickens fed a low-metabolizable energy diet