T Cell Receptor Is Required for Differentiation, but Not Maintenance, of Intestinal CD4+ Intraepithelial Lymphocytes

Bilate, Angelina M.; London, Mariya; Castro, Tiago B. R.; Mesin, Luka; Bortolatto, Juliana; Kongthong, Suppawat; Harnagel, Audrey; Victora, Gabriel D.; Mucida, Daniel

doi:10.1016/j.immuni.2020.09.003

Cited by 60 publications

(68 citation statements)

References 63 publications

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“…This suggests that there may be a connection with the bacterial burden of the gut microbiota, which is an essential component for MHC II expression in IECs and DP IEL development ( Cervantes-Barragan et al, 2017 ; Koyama et al, 2019 ; Sujino et al, 2016 ). The role of TCR engagement for the development of DP IELs has recently been suggested by a study by Bilate et al, in which the researchers found that TCR signaling is required for the differentiation of SP IELs to DP IELs but not for the maintenance of DP IELs ( Bilate et al, 2020 ). Furthermore, the inducible deletion of MHC II in IECs down-regulated the development of DP IELs.…”

Section: Resultsmentioning

confidence: 99%

“…PD-1 signaling blocks T cell activation signals induced by the TCR and CD28 costimulatory molecule ( Hui et al, 2017 ; Sun et al, 2018 ). Interestingly, the expression of Nur77, a downstream molecule of TCR signaling, was inversely correlated with the acquisition of CD8αα, suggesting that the dampening of TCR signaling precedes DP IEL differentiation ( Bilate et al, 2020 ). Considering that T cell–intrinsic PD-1 signaling is required for DP IEL differentiation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Niche-specific MHC II and PD-L1 regulate CD4+CD8αα+ intraepithelial lymphocyte differentiation

Moon

Park

Hyeon

et al. 2021

Journal of Experimental Medicine

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Conventional CD4+ T cells are differentiated into CD4+CD8αα+ intraepithelial lymphocytes (IELs) in the intestine; however, the roles of intestinal epithelial cells (IECs) are poorly understood. Here, we showed that IECs expressed MHC class II (MHC II) and programmed death–ligand 1 (PD-L1) induced by the microbiota and IFN-γ in the distal part of the small intestine, where CD4+ T cells were transformed into CD4+CD8αα+ IELs. Therefore, IEC-specific deletion of MHC II and PD-L1 hindered the development of CD4+CD8αα+ IELs. Intracellularly, PD-1 signals supported the acquisition of CD8αα by down-regulating the CD4-lineage transcription factor, T helper–inducing POZ/Krüppel-like factor (ThPOK), via the Src homology 2 domain–containing tyrosine phosphatase (SHP) pathway. Our results demonstrate that noncanonical antigen presentation with cosignals from IECs constitutes niche adaptation signals to develop tissue-resident CD4+CD8αα+ IELs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Niche-specific MHC II and PD-L1 regulate CD4+CD8αα+ intraepithelial lymphocyte differentiation

Moon

Park

Hyeon

et al. 2021

Journal of Experimental Medicine

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“…Hou et al inferred that antigen experience leads the TRB repertoire of memory T cells skewed. Bilate et al. (2020) found that intestinal CD4 + intraepithelial lymphocytes differentiation was always accompanied by clonal restriction, suggesting that TCR and local antigen presentation is required by differentiation of this subset of T cells.…”

Section: Discussionmentioning

confidence: 97%

Characteristics of T-cell receptor repertoire of stem cell-like memory CD4+ T cells

Wang

Liu

et al. 2021

PeerJ

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Stem cell-like memory T cells (Tscm) combine phenotypes of naïve and memory. However, it remains unclear how T cell receptor (TCR) characteristics contribute to heterogeneity in Tscm and other memory T cells. We compared the TCR-beta (TRB) repertoire characteristics of CD4+ Tscm with those of naïve and other CD4+ memory (Tm) in 16 human subjects. Compared with Tm, Tscm had an increased diversity across all stretches of TRB repertoire structure, a skewed gene usage, and a shorter length distribution of CDR3 region. These distinctions between Tscm and Tm were enlarged in top1000 abundant clonotypes. Furthermore, top1000 clonotypes in Tscm were more public than those in Tm and grouped in more clusters, implying more epitope types recognized by top1000 clonotypes in Tscm. Importantly, self-reactive clonotypes were public and enriched in Tscm rather than Tm, of type one diabetes patients. Therefore, this study highlights the unique features of Tscm different from those of other memory subsets and provides clues to understand the physiological and pathological functions of Tscm.

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“…The development of CD4 + CD8αα + IELs is also affected by microbiota members, such as Lactobacillus reuteri [ 180 ]. The microbiota‐driven expression of MHC‐II and programmed death‐ligand 1 (PD‐L1) by IECs is required for the differentiation of CD4 T cells to become CD4 + CD8αα + IELs [ 181 , 182 ].…”

Section: Bidirectional Interactions Between the Adaptive Immune System And The Microbiomementioning

confidence: 99%

Non‐zero‐sum microbiome immune system interactions

Tuganbaev

Honda

2021

Eur J Immunol

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Fundamental asymmetries between the host and its microbiome in enzymatic activities and nutrient storage capabilities have promoted mutualistic adaptations on both sides. As a result, the enteric immune system has evolved so as not to cause a zero-sum sterilization of non-self, but rather achieve a non-zero-sum self-reinforcing cooperation with its evolutionary partner the microbiome. In this review, we attempt to integrate the accumulated knowledge of immune-microbiome interactions into an evolutionary framework and trace the pattern of positive immune-microbiome feedback loops across epithelial, enteric nervous system, innate, and adaptive immune circuits. Indeed, the immune system requires commensal signals for its development and function, and reciprocally protects the microbiome from nutrient shortage and pathogen outgrowth. In turn, a healthy microbiome is the result of immune system curatorship as well as microbial ecology. The paradigms of host-microbiome asymmetry and the cooperative nature of their interactions identified in the gut are applicable across all tissues influenced by microbial activities. Incorporation of immune system influences into models of microbiome ecology will be a step forward toward defining what constitutes a healthy human microbiome and guide discoveries of novel host-microbiome mutualistic adaptations that may be harnessed for the promotion of human health.

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T Cell Receptor Is Required for Differentiation, but Not Maintenance, of Intestinal CD4+ Intraepithelial Lymphocytes

Cited by 60 publications

References 63 publications

Niche-specific MHC II and PD-L1 regulate CD4+CD8αα+ intraepithelial lymphocyte differentiation

Niche-specific MHC II and PD-L1 regulate CD4+CD8αα+ intraepithelial lymphocyte differentiation

Characteristics of T-cell receptor repertoire of stem cell-like memory CD4+ T cells

Non‐zero‐sum microbiome immune system interactions

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