CD4+CD25+Foxp3+ regulatory T cells optimize diversity of the conventional T cell repertoire during reconstitution from lymphopenia.
The functional capacity of the adaptive immune system is dependent on the size and the diversity of the T cell population. In states of lymphopenia, T cells are driven to proliferate to restore the T cell population size. However, different T cell clones proliferate at different rates, and some T cells experience burst-like expansion called spontaneous lymphopenia-induced proliferation (LIP). These T cells are likely receiving stimulation from cognate Ags and are most responsible for inflammatory pathology that can emerge in lymphopenic states. Foxp3(+) regulatory T cells (Tregs) selectively inhibit spontaneous LIP, which may contribute to their ability to prevent lymphopenia-associated autoimmunity. We hypothesized that another potential negative consequence of unrestrained spontaneous LIP is constriction of the total T cell repertoire. We demonstrate that the absence of Foxp3(+) Tregs during the period of immune reconstitution results in the development of TCR repertoire "holes" and the loss of Ag-specific responsiveness to infectious microorganisms. In contrast, the presence of Tregs during the period of immune reconstitution preserves optimal TCR diversity and foreign Ag responsiveness. This finding contrasts with the generally accepted immunosuppressive role of Tregs and provides another example of Treg activity that actually enhances immune function.
Winstead
Colleen J
CJ
Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55414, USA.
Reilly
Cavan S
CS
Moon
James J
JJ
Jenkins
Marc K
MK
Hamilton
Sara E
SE
Jameson
Stephen C
SC
Way
Sing Sing
SS
Khoruts
Alexander
A
D019264:Adoptive Transfer; D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis*; D049109:Cell Proliferation; D022801:Complementarity Determining Regions / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D008231:Lymphopenia / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation
D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit