How decreasing T cell signaling unexpectedly results in autoimmunity.

In this issue of JEM, Tanaka et al. (2022. J.

Antigen-specific depletion of CD4 T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity.

Both higher- and lower-affinity self-reactive CD4 T cells are expanded in autoimmunity; however, their individual contribution to disease remains unclear. We addressed this question using peptide-MHCII chimeric antigen receptor (pMHCII-CAR) T cells to specifically deplete peptide-reactive T cells in mice. Integration of improvements in CAR engineering with TCR repertoire analysis was critical for interrogating in vivo the role of TCR affinity in autoimmunity.

Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections.

Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct-STL was vertically transmitted without negative health effects in wild-type mice.

Homeostasis of Naive and Memory T Lymphocytes.

Conventional CD4 and CD8 T lymphocytes comprise a mixture of naive and memory cells. Generation and survival of these T-cell subsets is under strict homeostatic control and reflects contact with self-major histocompatibility complex (MHC) and certain cytokines. Naive T cells arise in the thymus via T-cell receptor (TCR)-dependent positive selection to self-peptide/MHC complexes and are then maintained in the periphery through self-MHC interaction plus stimulation via interleukin-7 (IL-7).

Gut Helicobacter presentation by multiple dendritic cell subsets enables context-specific regulatory T cell generation.

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103 gut dendritic cells (DCs), yet their role in commensal-reactive pTreg development is unclear. Using two Helicobacterspecific T cell receptor (TCR) transgenic mouse lines, we found that both CD103 and CD103 migratory, but not resident, DCs from the colon-draining mesenteric lymph node presented Helicobacter antigens to T cells ex vivo. Loss of most CD103 migratory DCs in vivo using murine genetic models did not affect the frequency of Helicobacter-specific pTreg cell generation or induce compensatory tolerogenic changes in the remaining CD103 DCs.

Author Correction: Requirements for the differentiation of innate T-bet memory-phenotype CD4 T lymphocytes under steady state.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Requirements for the differentiation of innate T-bet memory-phenotype CD4 T lymphocytes under steady state.

CD4 T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4 T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bet, T-bet, and T-bet subsets, with innate, Th1-like effector activity exclusively associated with T-bet cells.

New insights on T-cell self-tolerance.

Self-tolerance of T cells is maintained by a combination of thymic negative selection and suppression by T regulatory cells (Tregs); both processes are driven by recognition of self MHC ligands. Treg function ensures that most T cells remain quiescent as naïve cells, but enables some T cells to proliferate and differentiate into cells with a memory phenotype (MP). In this review, we discuss how Tregs shape this compartmentalization of T cells into subsets of naïve and MP T cells.

Interleukin-2/antibody complex expanding Foxp3 regulatory T cells exacerbates Th2-mediated allergic airway inflammation.

Foxp3＋ regulatory CD4＋ T (Treg) cells play an essential role in preventing overt immune responses against self and innocuous foreign antigens. Selective expansion of endogenous Treg cells in response to the administration of interleukin (IL)-2/antibody complex, such as the IL-2/JES6-1 complex (IL-2C) in mice, is considered an attractive therapeutic approach to various immune disorders. Here, we investigated the therapeutic potential of IL-2C in allergic airway inflammation models.

Segmented Filamentous Bacteria Induce Divergent Populations of Antigen-Specific CD4 T Cells in the Small Intestine.

CD4 T cells differentiate into RORγt/IL-17A-expressing cells in the small intestine following colonization by segmented filamentous bacteria (SFB). However, it remains unclear whether SFB-specific CD4 T cells can differentiate directly from naïve precursors, and whether their effector differentiation is solely directed towards the Th17 lineage. In this study, we used adoptive T cell transfer experiments and showed that naïve CD4 T cells can migrate to the small intestinal lamina propria (sLP) and differentiate into effector T cells that synthesize IL-17A in response to SFB colonization.

Unregulated antigen-presenting cell activation by T cells breaks self tolerance.

T cells proliferate vigorously following acute depletion of CD4 Foxp3 T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation.

Cell surface polysaccharides of induce the generation of Foxp3 regulatory T cells.

Dysregulation of intestinal microflora is linked to inflammatory disorders associated with compromised immunosuppressive functions of Foxp3 T regulatory (T) cells. Although mucosa-associated commensal microbiota has been implicated in T generation, molecular identities of the "effector" components controlling this process remain largely unknown. Here, we have defined as a potent inducer of Foxp3 T cells with diverse T cell receptor specificity to dietary antigens, commensal bacteria, and itself.

Phenotypic and Functional Changes of Peripheral Ly6C T Regulatory Cells Driven by Conventional Effector T Cells.

A relatively high affinity/avidity of T cell receptor (TCR) recognition for self-peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune-suppressive in their function under steady state condition. We show here that based on the previously defined heterogeneity in the phenotype of peripheral Treg populations, Ly6C expression on Treg marks a lower degree of activation, proliferation, and differentiation status as well as functional incompetence.

Dendritic cell expression of the signaling molecule TRAF6 is required for immune tolerance in the lung.

Immune tolerance in the lung is important for preventing hypersensitivity, such as allergic asthma. Maintenance of tolerance in the lung is established by coordinated activities of poorly understood cellular and molecular mechanisms, including participation of dendritic cells (DCs). We have previously identified DC expression of the signaling molecule TRAF6 as a non-redundant requirement for the maintenance of immune tolerance in the small intestine of mice.

Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine.

Dietary antigens are normally rendered nonimmunogenic through a poorly understood "oral tolerance" mechanism that involves immunosuppressive regulatory T (Treg) cells, especially Treg cells induced from conventional T cells in the periphery (pTreg cells). Although orally introducing nominal protein antigens is known to induce such pTreg cells, whether a typical diet induces a population of pTreg cells under normal conditions thus far has been unknown. By using germ-free mice raised and bred on an elemental diet devoid of dietary antigens, we demonstrated that under normal conditions, the vast majority of the small intestinal pTreg cells are induced by dietary antigens from solid foods.

Microbiota-Independent Ameliorative Effects of Antibiotics on Spontaneous Th2-Associated Pathology of the Small Intestine.

We have previously generated a mouse model of spontaneous Th2-associated disease of the small intestine called TRAF6ΔDC, in which dendritic cell (DC)-intrinsic expression of the signaling mediator TRAF6 is ablated. Interestingly, broad-spectrum antibiotic treatment ameliorates TRAF6ΔDC disease, implying a role for commensal microbiota in disease development. However, the relationship between the drug effects and commensal microbiota status remains to be formally demonstrated.