Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacterial infections

We have reported a new innate-like CD4 T cell population that expresses cell surface makers of effector/memory cells and produce Th1 and Th2 cytokines immediately upon activation. Unlike conventional CD4 T cells that are selected by thymic epithelial cells, these CD4 T cells, named T-CD4 T cells, are selected by MHC class II expressing thymocytes. Previously, we showed that the presence of T-CD4 T cells protected mice from airway inflammation suggesting an immune regulatory role of T-CD4 T cells. To further understand the function of T-CD4 T cells, we investigated immune responses mediated by T-CD4 T cells during bacterial infection because the generation of antigen specific CD4 T cells contributes to clearance of infection and for the development of immune memory. The current study shows a suppressive effect of T-CD4 T cells on both CD8 and CD4 T cell-mediated immune responses during Listeria and Helicobacter infections. In the mouse model of Listeria monocytogenes infection, T-CD4 T cells resulted in decreasedfrequency of Listeria-specific CD8 T cells and the killing activity of them. Furthermore, mice with T-CD4 T cells developed poor immune memory, demonstrated by reduced expansion of antigen-specific T cells and high bacterial burden upon re-infection. Similarly, the presence of T-CD4 T cells suppressed the generation of antigen-specific CD4 T cells in Helicobacter pylori infected mice. Thus, our studies reveal a novel function of T-CD4 T cells in sup-pressing anti-bacterial immunity.

Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE

Multiple sclerosis(MS)is a chronic inflammatory disease of the central nervous system(CNS)in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons.A hallmark of MS and its animal model,experimental autoimmune encephalomyelitis(EAE),is autoimmunity against proteins of the myelin sheath.Most studies in this field have focused on the roles of CD4^(+)T lymphocytes,which form part of the adaptive immune system as both mediators and regulators in disease pathogenesis.Consequently,the treatments for MS often target the inflammatory CD4^(+)T-cell responses.However,many other lymphocyte subsets contribute to the pathophysiology of MS and EAE,and these subsets include CD8^(+)T cells and B cells of the adaptive immune system,lymphocytes of the innate immune system such as natural killer cells,and subsets of innate-like T and B lymphocytes such asγδT cells,natural killer T cells,and mucosal-associated invariant T cells.Several of these lymphocyte subsets can act as mediators of CNS inflammation,whereas others exhibit immunoregulatory functions in disease.Importantly,the efficacy of some MS treatments might be mediated in part by effects on lymphocytes other than CD4^(+)T cells.Here we review the contributions of distinct subsets of lymphocytes on the pathogenesis of MS and EAE,with an emphasis on lymphocytes other than CD4^(+)T cells.A better understanding of the distinct lymphocyte subsets that contribute to the pathophysiology of MS and its experimental models will inform the development of novel therapeutic approaches.

Regulatory functions of innate-like B cells

Innate-like B cells （ILBs） are heterogeneous populations of unconventional B cells with innate sensing and responding properties. ILBs in mice are composed of B1 cells, marginal zone （MZ） B cells and other related B cells. ILBs maintain natural IgM levels at steady state, and after innate activation, they can rapidly acquire immune regulatory activities through the secretion of natural IgM and IL-IO. Thus, ILBs constitute an important source of IL-lO-producing regulatory B cells （Bregs）, which have been shown to play critical roles in autoimmunity, inflammation and infection. The present review highlights the latest advances in the field of ILBs and focuses on their regulatory functions. Understanding the regulatory activities of ILBs and their underlying mechanisms could open new avenues in manipulating their functions in inflammatory, infectious and other relevant diseases.

Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease

Mucosal-associated invariant T(MAIT)cells have been described in liver and nonliver diseases,and they have been ascribed antimicrobial,immune regulatory,protective,and pathogenic roles.The goals of this review are to describe their biological properties,indicate their involvement in chronic liver disease,and encourage investigations that clarify their actions and therapeutic implications.English abstracts were identified in PubMed by multiple search terms,and bibliographies were developed.MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines.Diverse pro-inflammatory,anti-inflammatory,and immune regulatory cytokines are released;infected cells are eliminated;and memory cells emerge.Circulating MAIT cells are hyper-activated,immune exhausted,dysfunctional,and depleted in chronic liver disease.This phenotype lacks disease-specificity,and it does not predict the biological effects.MAIT cells have presumed protective actions in chronic viral hepatitis,alcoholic hepatitis,non-alcoholic fatty liver disease,primary sclerosing cholangitis,and decompensated cirrhosis.They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis.Local factors in the hepatic microenvironment(cytokines,bile acids,gut-derived bacterial antigens,and metabolic by-products)may modulate their response in individual diseases.Investigational manipulations of function are warranted to establish an association with disease severity and outcome.In conclusion,MAIT cells constitute a disease-nonspecific,immune response to chronic liver inflammation and infection.Their pathological role has been deduced from their deficiencies during active liver disease,and future investigations must clarify this role,link it to outcome,and explore therapeutic interventions.

Innate lymphocytes:pathogenesis and therapeutic targets of liver diseases and cancer

The liver is a lymphoid organ with unique immunological properties,particularly,its predominant innate immune system.The balance between immune tolerance and immune activity is critical to liver physiological functions and is responsible for the sensitivity of this organ to numerous diseases,including hepatotropic virus infection,alcoholic liver disease,nonalcoholic fatty liver disease,autoimmune liver disease,and liver cancer,which are major health problems globally.In the past decade,with the discovery of liver-resident natural killer cells,the importance of innate lymphocytes with tissue residency has gradually become the focus of research.In this review,we address the current knowledge regarding hepatic innate lymphocytes with unique characteristics,including NK cells,ILC1/2/3s,NKT cells,γδ T cells,and MAIT cells,and their potential roles in liver homeostasis maintenance and the progression of liver diseases and cancer.A better understanding of the immunopathogenesis of hepatic innate lymphocytes will be helpful for proposing effective treatments for liver diseases and cancer.

Adiponectin:a versatile player of innate immunity

Adiponectin acts as a key regulator of the innate immune system and plays a major role in the progression of inflammation and metabolic disorders.Macrophages and monocytes are representative components of the innate immune system,and their proliferation,plasticity,and polarization are a key component of metabolic adaption.Innate-like lymphocytes such as group 2 innate lymphoid cells(ILC2s),natural killer T(NKT)cells,and gamma delta T(gd T)cells are also members of the innate immune system and play important roles in the development of obesity and its related diseases.Adiponectin senses metabolic stress and modulates metabolic adaption by targeting the innate immune system under physiological and pathological conditions.Defining the mechanisms underlying the role of adiponectin in regulating innate immunity is crucial to adiponectin-based therapeutic intervention.