Wang, CJ;
Heuts, F;
Ovcinnikovs, V;
Wardzinski, L;
Bowers, C;
Schmidt, EM;
Kogimtzis, A;
... Walker, LS; + view all
(2015)
CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement.
Proceedings of the National Academy of Sciences of the U S A
, 112
(2)
pp. 524-529.
10.1073/pnas.1414576112.
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Abstract
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 (TFH) 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 TFH 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 TFH differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered TFH 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 TFH differentiation by graded control of CD28 engagement.
| Type: | Article |
|---|---|
| Title: | CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1414576112 |
| Publisher version: | http://dx.doi.org/10.1073/pnas.1414576112 |
| Language: | English |
| Additional information: | Freely available online through the PNAS open access option. Copyright © 2015 National Academy of Sciences. |
| Keywords: | CD28, CTLA-4, T cell, autoimmunity, costimulation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1459989 |
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