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Autoimmune regulator (Aire) and TGF‐β signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)‐like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFβRII Aire−/− mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA‐seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFβRII Aire−/− mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti‐CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA‐seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice developed an autoreactive CD8+ T‐cell‐mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH‐PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

[α.sub.4][β.sub.7] integrin-expressing [CD4.sup.+] T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-[α.sub.4][β.sub.7] monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with [SIV.sub.mac251]. In treated animals that became infected, the GALT was significantly protected from infection and [CD4.sup.+] T cell numbers were maintained in both the blood and the GALT. Thus, targeting [α.sub.4][β.sub.7] reduces mucosal transmission of SIV in macaques., [CD4.sup.+] T cells residing in GALT are a predominant target of HIV and SIV during the acute phase of infection, and their depletion has been implicated in HIV and SIV [...]

CD[4.sup.+] T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of [...]

Primary biliary cholangitis (PBC), an organ-specific autoimmune disease, is characterized by injury to small bile ducts, inflammatory cell infiltrates within the liver, progressive cholestasis, and in some cases, cirrhosis with unclear pathogenesis. We aimed to clarify the importance role of hepatic immunce cells in the pathogenesis of human and experimental PBC.The dominant-negative TGFβ receptor type II transgenic (dnTGFβRII) mice, a well-studied and established murine model of PBC were used to identify changes of immune cells, especially the pathogenic CD8+ T cells. The high-throughput single-cell RNA sequencing technology were applied and found functional heterogeneity among the hepatic CD8+ T cells subsets in dnTGFβRII mice. CD8+ T cells were confirmed the key cells leading to the pathogenesis of PBC in dnTGFβRII mice, and identified the terminally differentiated CD8αα T cells and CD8αβ T cell subsets in the liver of dnTGFβRII mice. While terminally differentiated CD8αα T cells have higher cytokine production ability and cytotoxicity, the terminally differentiated CD8αβ T cells retain their proliferative profile. Our work suggests that there are developmental and differentiated trajectories of pathogenic CD8+ T cell subsets in the pathogenesis of PBC. A further clarification of their roles would be helpful to our understanding of the pathogenesis of PBC and may potentially lead to identifying novel therapeutic modalities. [ABSTRACT FROM AUTHOR]

Naturally SIV-infected sooty mangabeys (SMs) remain asymptomatic despite high virus replication. Elucidating the mechanisms underlying AIDS resistance of SIV-infected SMs may provide crucial information to better understand AIDS pathogenesis. In this study, we assessed the determinants of set-point viremia in naturally SIV-infected SMs, i.e., immune control of SIV replication versus target cell limitation. We depleted [CD4.sup.+] T cells in 6 naturally SIV-infected SMs by treating with humanized anti-CD4 mAb (Cdr-OKT4A-huIgG1). [CD4.sup.+] T cells were depleted almost completely in blood and BM and at variable levels in mucosal tissues and LNs. No marked depletion of [CD14.sup.+] monocytes was observed. Importantly, [CD4.sup.+] T cell depletion was associated with a rapid, significant decline in viral load, which returned to baseline level at day 30-45, coincident with an increased fraction of proliferating and activated [CD4.sup.+] T cells. Throughout the study, virus replication correlated with the level of proliferating [CD4.sup.+] T cells. [CD4.sup.+] T cell depletion did not induce any changes in the fraction of Tregs or the level of SIV-specific [CD8.sup.+] T cells. Our results suggest that the availability of activated [CD4.sup.+] T cells, rather than immune control of SIV replication, is the main determinant of set-point viral load during natural SIV infection of SMs., Introduction The HIV epidemic in humans arose after zoonotic transmission of simian [CD4.sup.+] T cell tropic lentiviruses, which naturally infect a range of African monkey host species and are now [...]