No abstract

Generation of a Nur77 reporter mouse is used to demonstrate TCR signal strength during thymic selection and peripheral maintenance of conventional and nonconventional T cell subsets and presents a novel tool for studying antigen receptor activation in vivo.

The fate of developing T cells is specified by interactions of their antigen receptor with self-peptide/MHC complexes displayed by thymic antigen presenting cells (APCs). Various thymic APCs subsets are strategically positioned in particular thymic microenvironments and orchestrate the selection of a functional and self-tolerant T cell repertoire. Here, we will review the different strategies that these APCs employ to sample and process self-antigens and thereby generate partly unique, ‘idiosyncratic’ peptide/MHC ligandomes. We will discuss how the particular composition of these APC-subset-specific peptide/MHC ligandomes not only shapes the T cell repertoire in the thymus, but may also indelibly imprint the behavior of mature T cells in the periphery.

iNKT cells can produce high levels of IL-4 early during infection. However, indirect evidence suggests they may produce this immunomodulatory cytokine in the steady state. Through intracellular staining for transcription factors, we define 3 subsets of iNKT cells that produce distinct cytokines (NKT1, NKT2, and NKT17), which represent diverse lineages and not developmental stages as previously thought. These subsets exhibit substantial inter-strain variation in numbers. In several strains, including BALB/c, NKT2 cells are abundant and stimulated by self-ligands to produce IL-4. In these strains, steady state IL-4 conditions CD8 T cells to become “memory-like”, increases serum IgE levels, and causes dendritic cells to produce chemokines. Thus iNKT cell derived IL-4 alters immune properties under normal steady state conditions.

Cell-mediated immunity critically depends on lymphocyte localization at sites of infection. While some memory T cells recirculate, a distinct lineage (resident memory T cells; TRM) are embedded in non-lymphoid tissues (NLTs) and mediate potent protective immunity. However, the defining transcriptional basis for TRM establishment is unknown. We report that CD8+ TRM cells lacked expression of the transcription factor KLF2 and its target gene S1pr1 (encoding sphingosine 1-phosphate receptor 1). Forced S1PR1 expression prevented establishment of TRM. Cytokines inducing TRM phenotype (including TGF-β, IL-33 and TNF) provoked KLF2 downregulation in a phosphatidylinositol-3-OH kinase (PI(3)K)–Akt-dependent pathway, suggesting environmental regulation. Hence KLF2 and S1PR1 regulation provides a switch, dictating whether CD8+ T cells commit to the recirculating or tissue resident memory populations.

Differentiation and maintenance of recirculating effector memory CD8 T cells (TEM) depends on prolonged cognate antigen stimulation. Whether similar pathways of differentiation exist for recently identified tissue-resident effector memory T cells (TRM), which contribute to rapid local protection upon pathogen re-exposure, is unknown. Memory CD8αβ+ T cells within small intestine epithelium are well-characterized examples of TRM and they maintain a long-lived effector-like phenotype that is highly suggestive of persistent antigen stimulation. This study sought to define the sources and requirements for prolonged Ag-stimulation in programming this differentiation state, including local stimulation via cognate or cross-reactive antigens derived from pathogens, microbial flora, or dietary proteins. Contrary to expectations, we found that prolonged cognate Ag-stimulation was dispensable for intestinal TRM ontogeny. In fact, chronic antigenic stimulation skewed differentiation away from the canonical intestinal T cell phenotype. Resident memory signatures, CD69 and CD103, were expressed in many non-lymphoid tissues including intestine, stomach, kidney, reproductive tract, pancreas, brain, heart, and salivary gland, and could be driven by cytokines. Moreover, TGFβ driven CD103 expression was required for TRM maintenance within intestinal epithelium in vivo. Thus, induction and maintenance of long-lived effector-like intestinal TRM differed from classic models of TEM ontogeny, and were programmed through a novel location-dependent pathway that was required for the persistence of local immunological memory.

A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens. This selection occurs predominantly in the thymus, where lymphocyte precursors first assemble a surface receptor. In this review we summarize the current state of the field regarding the natural ligands and molecular factors required for positive and negative selection and discuss a model for how these disparate outcomes can be signaled via the same receptor. We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated.

Langerhans cells (LCs) are antigen-presenting cells that reside in the epidermis of the skin and traffic to lymph nodes (LNs). The general role of these cells in skin immune responses is not clear because distinct models of LC depletion resulted in opposite conclusions about their role in contact hypersensitivity (CHS) responses. While comparing these models, we discovered a novel population of LCs that resides in the dermis and does not represent migrating epidermal LCs, as previously thought. Unlike epidermal LCs, dermal Langerin+ dendritic cells (DCs) were radiosensitive and displayed a distinct cell surface phenotype. Dermal Langerin+ DCs migrate from the skin to the LNs after inflammation and in the steady state, and represent the majority of Langerin+ DCs in skin draining LNs. Both epidermal and dermal Langerin+ DCs were depleted by treatment with diphtheria toxin in Lang-DTREGFP knock-in mice. In contrast, transgenic hLang-DTA mice lack epidermal LCs, but have normal numbers of dermal Langerin+ DCs. CHS responses were abrogated upon depletion of both epidermal and dermal LCs, but were unaffected in the absence of only epidermal LCs. This suggests that dermal LCs can mediate CHS and provides an explanation for previous differences observed in the two-model systems.