Btla Signaling in Conventional and Regulatory Lymphocytes Coordinately Tempers Humoral Immunity in the Intestinal Mucosa

Stienne, Caroline; Virgen-Slane, Richard; Elmén, Lisa; Veny, Marisol; Huang, Sarah X.L.; Nguyen, Jennifer; Chappell, Elizabeth; Balmert, M. Olivia; Shui, Jr-Wen; Hurchla, Michelle A.; Kronenberg, Mitchell; Peterson, Scott N.; Murphy, Kenneth M.; Ware, Carl F.; Šedý, John

doi:10.2139/ssrn.3766488

Cited by 2 publications

(3 citation statements)

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“…B6. Btla fl/fl mice [32,88] generated by us (M.K.) and were kindly provided by John R Šedý and Carl Ware (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States).…”

Section: Methodsmentioning

confidence: 99%

“…A T cell can express both BTLA and HVEM, and HVEM interactions with BTLA between cells, in trans , or cis interactions in which one cell expresses both binding partners, are inhibitory [30]. Consistent with its coinhibitory function, mice lacking BTLA develop systemic autoimmune disease and multiorgan lymphocytic infiltration [31]; they also have increased frequencies of T follicular helper cells in Peyer’s patches and increased IgG and IgA, the latter affecting the homeostasis of gut bacteria [32]. In contrast, Cd5 −/− mice remain relatively healthy, even in late-life [33].…”

Section: Introductionmentioning

confidence: 99%

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Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants

Adegoke,

Thangavelu,

Chou

et al. 2024

Preprint

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Several coinhibitory receptors are upregulated upon activation, whereas a small number of coinhibitory receptors are expressed constitutively by naive T cells. The relationship between constitutively expressed coinhibitors is unknown. We found an inverse relationship between two constitutively expressed coinhibitors, CD5 and BTLA; BTLA expression was low in the thymus and high in the periphery, corresponding respectively with high and low CD5 expression. Germline or induced deletion of Btla in somatic cells demonstrated a causal relationship between BTLA expression and CD5 levels in T cells of central and peripheral lymphoid tissues. The effect of BTLA on CD5 expression on thymic and peripheral CD4 T cells was due to BTLA signaling, rather than signaling by its ligand, the herpes virus mediator (HVEM). Regulation was maintained in mice with a non-signaling HVEM mutant but was lost in Tnfrsf14-/- (Hvem-/-) mice. Increased CD5 levels have been positively associated with increased recognition of self-peptide MHC complexes. Thus, control of CD5 expression by BTLA signals early in T cell ontogeny suggested that BTLA might be important for establishing self-tolerance in newly generated T cells. Consistent with this concept, we found that BTLA, as well as the inducible coinhibitor PD-1, were needed post thymic selection in recent thymic emigrants (RTE) to establish self-tolerance. RTE lacking BTLA caused a multiorgan autoimmune disease whose development required CD4 T cells and MHC class II. Together, our findings identify a negative regulatory pathway allowing constitutively expressed coinhibitory receptors to calibrate their expression in thymic T cell differentiation. Expression of constitutive and induced coinhibitory receptors is needed to establish tolerance in the periphery for RTE.

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“…B6. Btla fl/fl mice [32,88] generated by us (M.K.) and were kindly provided by John R Šedý and Carl Ware (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants

Adegoke,

Thangavelu,

Chou

et al. 2024

Preprint

Self Cite

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“…This is particularly difficult due to the shared transcriptional programme between Tfr cells and Treg/Tfh. The BTLA pathway may promote Tfr cells, and BTLA overexpression in rat kidney transplant models has a strong inhibitory effect on acute rejection (including TCMR and AbMR), possibly by promoting Tfr cells [30,31]. However, BTLA may have a number of roles on multiple immune cells.…”

Section: Therapeutically Targeting T Follicular Regulatory Cells In A...mentioning

confidence: 99%

Role of T follicular helper and T follicular regulatory cells in antibody-mediated rejection: new therapeutic targets?

Zhang

Sage²

2022

Current Opinion in Organ Transplantation

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Purpose of reviewAntibody-mediated rejection (AbMR) after solid organ transplantation is tightly controlled by multiple cells of the immune system. Tfh and Tfr cells are essential controllers of antibody responses making them putative targets for therapeutics. However, the mechanisms of how Tfh and Tfr cells regulate B cell and antibody responses are not completely understood. Here, we summarize recent studies elucidating the functions of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells as well as their possible roles in regulating AbMR in solid organ transplantation. Recent findingsNew tools have been developed to study the roles of Tfh and Tfr cells in specific disease states, including AbMR after solid organ transplantation. These tools suggest complex roles for Tfh and Tfr cells in controlling antibody responses. Nevertheless, studies in solid organ transplant rejection suggest that Tfh and Tfr cells may be high value targets for therapeutics. However, specific strategies to target these cells are still being investigated. SummaryAbMR is still a substantial clinical problem that restricts long-term survival after solid organ transplantation. Growing evidence has demonstrated a pivotal role for Tfh and Tfr cells in controlling AbMR. In addition to providing an early indication of rejection as a biomarker, targeting Tfh and Tfr cells as a therapeutic strategy offers new hope for alleviating AbMR.

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Btla Signaling in Conventional and Regulatory Lymphocytes Coordinately Tempers Humoral Immunity in the Intestinal Mucosa

Cited by 2 publications

References 0 publications

Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants

Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants

Role of T follicular helper and T follicular regulatory cells in antibody-mediated rejection: new therapeutic targets?

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