Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions

Abstract

Peripheral CD4 T cells in Vβ5 transgenic (Tg) C57BL/6J mice undergo tolerance to an endogenous superantigen encoded by mouse mammary tumor virus 8 (Mtv-8) by either deletion or T-cell receptor (TCR) revision. Revision is a process by which surface expression of the Vβ5 + TCR is down-regulated in response to Mtv-8 and recombination activating genes are expressed to drive rearrangement of the endogenous TCRβ locus, effecting cell rescue through the expression of a newly generated, non-self-reactive TCR. In an effort to identify the microenvironment in which revision takes place, we show here that the proportion of T follicular helper cells (Tfh) and production of high-affinity antibody during a primary response are increased in Vβ5 Tg mice in an Mtv-8-dependent manner. Revising T cells have a Tfh-like surface phenotype and transcription factor profile, with elevated expression of B-cell leukemia/lymphoma 6 (Bcl-6), CXC chemokine receptor 5, programmed death-1, and other Tfh-associated markers. Efficient revision requires Bcl-6 and is inhibited by B lymphocyte-induced maturation protein-1. Revision completes less efficiently in the absence of signaling lymphocytic activation molecule-associated protein although initiation proceeds normally. These data indicate that Tfh formation is required for the initiation of revision and germinal-center interactions for its completion. The germinal center is known to provide a confined space in which B-cell antigen receptors undergo selection. Our data extend the impact of this selective microenvironment into the arena of T cells, suggesting that this fluid structure also provides a regulatory environment in which TCR revision can safely take place.Rag-mediated recombination | T-cell tolerance

Regulatory T cells and co‐evolution of allele‐specific MHC recognition by the TCR

“…Over the past 25 years, the Germinal Centre has established itself as the main post‐antigenic site in the periphery for BCR and TCR ‘Receptor Mutation/Replacement Programs’ . This is generally overtly accepted for the rapid SHM of BCR Igs and thus their mutated and modified secreted antibodies.…”

“…All the indications are that the Germinal Centre‐mediated programme of RAG‐assisted ‘Receptor Mutation, Replacement, Revision’ as summed up by Nemazee and Weigert is not restricted to B cells. Thus, RAG‐assisted V replacement programmes, particularly the Ig VH segment to Ig VDH replacement process and secondary V[D]J rearrangements can also be orchestrated in T cells in Germinal Centres or the immediate cellular environment . Many V replacement/revision events, which depend on sequence homologies to RAG‐recognized embedded heptamers at the 3’ end of framework region 3 probably go undetected .…”

“…Over the past 25 years, the Germinal Centre has established itself as the main post-antigenic site in the periphery for BCR and TCR 'Receptor Mutation/Replacement Programs'. [30][31][32][33] This is generally overtly accepted for the rapid SHM of BCR Igs and thus their mutated and modified secreted antibodies. For B cells, Nemazee and Weigert 30 succinctly summarize 'Working together, receptor selection and clonal selection (in the GC) account for the astonishing rapidity of the somatic evolution of immune specificity'.…”

“…Thus, RAG-assisted V replacement programmes, particularly the Ig VH segment to Ig VDH replacement process 31,48-50 and secondary V[D]J rearrangements can also be orchestrated in T cells in Germinal Centres or the immediate cellular environment. 32,33,51 Many V replacement/revision events, which depend on sequence homologies to RAG-recognized embedded heptamers at the 3' end of framework region 3 probably go undetected. 30,31 Thus, 'VH replacement at the downstream heptamer is essentially "invisible," since most of the recipient gene is erased ".. a profound reason for underestimating the extent of VH editing .." of his type.…”

Functional Capacity of Memory Cells Cd8+ Under Lymphopenia Induced by Injection of Hydrocortisone

“…Существование такого механизма позволило бы организму сохранять широту репертуара Т-клеток для успешного иммунного ответа на другие антигены и мог-ло бы дать рациональное объяснение появлению в тиму-се клеток памяти. Такое объяснение вполне возможно ввиду накапливающихся данных о ревизии зрелого периферического репертуара Т-лимфоцитов [17]. Заключение В этой статье мы впервые показали, что лимфо-пения, вызванная введением мышам высокой (2,5 мг на животное) дозы гидрокортизона, позволяет обна-ружить аллоспецифические клетки памяти в тимусе животных, иммунизированных клетками аллогенных опухолей.…”