More pieces of the puzzle

Follicular helper T (T_FH) cells are a subset of CD4⁺ T cells that are confined to the B-cell areas of lymphoid organs and have a role in the selection of memory B cells or long-lived plasma cells that produce high-affinity antibodies. Now, three papers have broadened our understanding of T_FH cells, describing features of their functional development, their role in shaping antibody responses and how their dysfunction contributes to systemic autoimmunity.

In the first study, Fazilleau et al. examined the total antigen-specific T_H-cell compartment in the draining lymph nodes following protein vaccination. The antigen-specific T_H cells could be divided into three subsets: a T-zone-restricted B-lymphocyte-induced maturation protein 1 (BLIMP1)-expressing 'lymphoid' T_H-cell subset (CD62L^hiCXCR5^low), an 'emigrant' T_H-cell subset (CD62L^lowCXCR5^low) and a 'resident' T_H-cell subset (CD62L^lowCXCR5^hi) that uniquely expressed B-cell lymphoma 6 (BCL6) and had other features of T_FH cells. The authors then determined the relationship between the development of these T_H-cell subsets and the affinity and diversity of their T-cell receptors (TCRs). They found that naive CD4⁺ T cells that expressed TCRs with high affinity for antigen preferentially developed into T_FH cells. In addition, these T_FH cells had the strongest peptide–MHC class II binding and a more restricted TCR repertoire compared with the lymphoid or emigrant T_H cells. So, the strength of TCR binding is causally linked to the development of antigen-specific T_FH cells in vivo.

In the second study, Reinhardt and colleagues sought to determine the exact role for T_H-cell-derived cytokines in the selection of high-affinity antibodies and the induction of class switching in B cells. In response to infection, all interleukin-4 (IL-4)-producing T cells in the draining lymph nodes were restricted to the B-cell follicles and germinal centres and had a T_FH-cell phenotype. These IL-4-producing T_FH cells were phenotypically and functionally distinct from IL-4-producing T_H2 cells in the periphery. Further investigation showed that some T_FH cells formed conjugates with B cells undergoing immunoglobulin class switching; IL-4-producing T_FH cell–B-cell conjugates contained IgG1 transcripts, whereas interferon-γ-producing T_FH-cell–B-cell conjugates contained IgG2a transcripts. In addition, T_FH-cell-derived IL-4 was shown to be specifically required for the generation of high-affinity IgG1 antibodies. This study therefore shows that the production of cytokines by T_FH cells shapes the isotype and affinity of the antibody response.

In the third study, Linterman et al. determined the role of T_FH cells in systemic lupus erythematosus (SLE) using Roquin^san/san mice (roquin is a RING-type ubiquitin ligase that regulates mRNA stability in T cells). These mice develop a spontaneous SLE-like autoimmune disease with features that include autoantibody production, spontaneous germinal centre formation and high numbers of T_FH cells. The expansion of T_FH cells and the spontaneous formation of germinal centres were shown to be the result of a T_FH-cell-intrinsic defect in these mice. Deletion of SLAM-associated protein (SAP; required for germinal centre formation) in these mice resulted in a selective reduction in the number of T_FH cells, but not other T_H cells, and abrogated the spontaneous formation of germinal centres and the production of autoantibodies. By contrast, T_FH cells isolated from Roquin^san/san mice induced spontaneous germinal centre formation in wild-type mice. So, expansion of the T_FH-cell population and defective positive selection of germinal centre B cells has a role in the development of autoimmunity, possibly owing to reduced competition between B cells for T-cell help.

Together, these three papers provide us with a considerable advancement in our understanding of the differentiation and function of T_FH cells.