CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 2; pp. 524 - 529
• Main Authors: Wang, Chun Jing, Heuts, Frank, Ovcinnikovs, Vitalijs, Wardzinski, Lukasz, Bowers, Chantelle, Schmidt, Emily M., Kogimtzis, Alexandros, Kenefeck, Rupert, Sansom, David M., Walker, Lucy S. K.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.01.2015; National Acad Sciences
• Subjects: Adaptive Immunity; Animals; Antigens; Autoantibodies - biosynthesis; B7-1 Antigen - metabolism; B7-2 Antigen - metabolism; Biological Sciences; CD28 Antigens - deficiency; CD28 Antigens - genetics; CD28 Antigens - metabolism; Cell Differentiation - immunology; CTLA-4 Antigen - deficiency; CTLA-4 Antigen - genetics; CTLA-4 Antigen - metabolism; Cytotoxicity; Germinal Center - cytology; Germinal Center - immunology; Heterozygote; Ligands; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred BALB C; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Models, Immunological; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - immunology; CD28; CTLA-4; autoimmunity; costimulation; T cell
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1414576112

Significance The inhibitory protein cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is recognized as a crucial regulator of autoimmunity, but its precise mechanism of action is not yet fully understood. CTLA-4 can down-regulate expression of the costimulatory ligands CD80 and CD86 on antigen presenting cells, thereby reducing T-cell CD28 engagement. Here we demonstrate that quantitative changes in the level of CD28 engagement have functional consequences for T-cell differentiation toward follicular helper T cells (T FHs). These findings link CTLA-4 control of T-cell responses with the generation of high-affinity class-switched antibody responses. This generates an advanced conceptual framework for understanding the linked nature of CTLA-4 and CD28 functions and the role of this pathway in influencing autoimmunity. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4–deficient mice show spontaneous T-follicular helper (T FH) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti–CTLA-4 antibody in wild-type mice is sufficient to elicit T FH generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for T FH differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered T FH generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of T FH differentiation by graded control of CD28 engagement.