Receptor revision in CD4 T cells is influenced by follicular helper T cell formation and germinal-center interactions.
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.
Department of Immunology and Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98109.
Lauren E
LE
Higdon
Katherine A
KA
Deets
Travis J
TJ
Friesen
Kai-Yin
KY
Sze
Pamela J
PJ
Fink
D000818:Animals; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D015329:Gene Rearrangement, T-Lymphocyte / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D011995:Recombination, Genetic / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
D017931:DNA Primers; D011948:Receptors, Antigen, T-Cell
Rag-mediated recombination; T-cell tolerance