Abstract

B7/CD28 costimulation is required to generate functional mature CD4+CD25+Foxp3+ regulatory T cells in the thymus. However, its not known whether B7/CD28 costimulation is also required to maintain regulatory function in the periphery. We developed an experimental system in which B7/CD28 costimulation was available in the thymus to induce the generation of Foxp3+ Treg cells, but B7/CD28 costimulation was absent from the periphery where Treg cells resided. We discovered that persistent costimulation in peripheral lymphoid organ is required to maintain Treg cell hyporesponsiveness and regulatory function through maintaining high level CTLA-4 expression in Tregs. We also found that CTLA-4 in Tregs is closely localized under the cytoplasmic membrane and this unique distribution facilitates its efficient inhibition of TCR signaling and contributes to the induction of hyporesponsiveness and regulatory function in Tregs. Our results indicate that maintaining high level expression of CTLA-4 in Tregs by persistent costimulation is critical for Treg cell function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011112-04
Application #
8349334
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$390,914
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Pobezinsky, Leonid A; Etzensperger, Ruth; Jeurling, Susanna et al. (2015) Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Nat Immunol 16:517-24
Takada, Kensuke; Van Laethem, Francois; Xing, Yan et al. (2015) TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8(+) T cells. Nat Immunol 16:1069-76
Tai, Xuguang; Singer, Alfred (2014) Basis of Treg development in the thymus. Cell Cycle 13:501-2
Van Laethem, François; Tikhonova, Anastasia N; Pobezinsky, Leonid A et al. (2013) Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154:1326-41
Kimura, Motoko Y; Pobezinsky, Leonid A; Guinter, Terry I et al. (2013) IL-7 signaling must be intermittent, not continuous, during CD8? T cell homeostasis to promote cell survival instead of cell death. Nat Immunol 14:143-51
Tai, Xuguang; Erman, Batu; Alag, Amala et al. (2013) Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38:1116-28
Tai, Xuguang; Van Laethem, Francois; Pobezinsky, Leonid et al. (2012) Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells. Blood 119:5155-63
Adoro, Stanley; Park, Jung-Hyun; Singer, Alfred (2012) Coreceptor gene ""imprinting:"" a genetic solution to a developmental dilemma in T cells. Cell Cycle 11:833-4
Tikhonova, Anastasia N; Van Laethem, François; Hanada, Ken-ichi et al. (2012) ?? T cell receptors that do not undergo major histocompatibility complex-specific thymic selection possess antibody-like recognition specificities. Immunity 36:79-91
Van Laethem, François; Tikhonova, Anastasia N; Singer, Alfred (2012) MHC restriction is imposed on a diverse T cell receptor repertoire by CD4 and CD8 co-receptors during thymic selection. Trends Immunol 33:437-41

Showing the most recent 10 out of 14 publications