CTLA-4 Engagement Acts as a Brake on CD4+ T Cell Proliferation and Cytokine Production but Is Not Required for Tuning T Cell Reactivity in Adaptive Tolerance

• Published in: The Journal of immunology (1950) 2004-12, Vol.173 (12), p.7239-7248
• Main Authors: Inobe, Manabu, Schwartz, Ronald H
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antigens, CD; Antigens, Differentiation - genetics; Antigens, Differentiation - immunology; Antigens, Differentiation - metabolism; Antigens, Differentiation - physiology; Antigens, Differentiation, T-Lymphocyte - biosynthesis; CD3 Complex - genetics; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - transplantation; Cell Division - genetics; Cell Division - immunology; Cell Proliferation; Columbidae; CTLA-4 Antigen; Cytochromes c - immunology; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Down-Regulation - genetics; Down-Regulation - immunology; Growth Inhibitors - deficiency; Growth Inhibitors - genetics; Growth Inhibitors - immunology; Growth Inhibitors - metabolism; Immunity, Innate - genetics; Lymphocyte Activation - genetics; Mice; Mice, Inbred A; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Resting Phase, Cell Cycle - genetics; Resting Phase, Cell Cycle - immunology; Self Tolerance - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.173.12.7239

Adaptive tolerance is the physiologic down-regulation of T cell responsiveness in the face of persistent antigenic stimulation. In this study, we examined the role of CTLA-4 in this process using CTLA-4-deficient and wild-type TCR transgenic, Rag2(-/-), CD4(+) T cells transferred into a T cell-deficient, Ag-expressing host. Surprisingly, we found that the tuning process of adoptively transferred T cells could be induced and the hyporesponsive state maintained in the absence of CTLA-4. Furthermore, movement to a deeper state of anergy following restimulation in vivo in a second Ag-bearing host was also unaffected. In contrast, CTLA-4 profoundly inhibited late T cell expansion in vivo following both primary and secondary transfers, and curtailed IL-2 and IFN-gamma production. Removal of this braking function in CTLA-4-deficient mice following Ag stimulation may explain their lymphoproliferative dysregulation.