T cell factor-1 controls the lifetime of CD4+ CD8+ thymocytes in vivo and distal T cell receptor α-chain rearrangement required for NKT cell development

• Published in: PloS one 2014-12, Vol.9 (12), p.e115803-e115803
• Main Authors: Sharma, Archna, Berga-Bolaños, Rosa, Sen, Jyoti Misra
• Format: Article
• Language: English
• Subjects: Adaptive control; Aging; Animals; Bcl-x protein; Biology and Life Sciences; Cancer; CD4 antigen; CD4 Antigens - immunology; CD8 antigen; CD8 Antigens - immunology; Cofactors; Ectopic expression; Flow cytometry; Gene Deletion; Gene expression; Gene rearrangement; Hepatocyte nuclear factor 1; Immune system; Inflammation; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Natural killer cells; Natural Killer T-Cells - cytology; Natural Killer T-Cells - immunology; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; T cell receptors; T Cell Transcription Factor 1 - genetics; T Cell Transcription Factor 1 - immunology; T-cell receptor; Thymocytes; Thymocytes - cytology; Thymocytes - immunology; Transcription factors; V(D)J Recombination
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0115803

Natural killer T (NKT) cells are a component of innate and adaptive immune systems implicated in immune, autoimmune responses and in the control of obesity and cancer. NKT cells develop from common CD4+ CD8+ double positive (DP) thymocyte precursors after the rearrangement and expression of T cell receptor (TCR) Vα14-Jα18 gene. Temporal regulation and late appearance of Vα14-Jα18 rearrangement in immature DP thymocytes has been demonstrated. However, the precise control of lifetime of DP thymocytes in vivo that enables distal rearrangements remains incompletely defined. Here we demonstrate that T cell factor (TCF)-1, encoded by the Tcf7 gene, is critical for the extended lifetime of DP thymocytes. TCF-1-deficient DP thymocytes fail to undergo TCR Vα14-Jα18 rearrangement and produce significantly fewer NKT cells. Ectopic expression of Bcl-xL permits Vα14-Jα18 rearrangement and rescues NKT cell development. We report that TCF-1 regulates expression of RORγt, which regulates DP thymocyte survival by controlling expression of Bcl-xL. We posit that TCF-1 along with its cofactors controls the lifetime of DP thymocytes in vivo.