T cells

B cell help

T cells develop in the thymus, where they undergo a selection process called central tolerance. Only cells able to interact with molecules from the major histocompatibility complex, lacking high affinity for self-antigens, survive. This ensures that self-reactive T cells are relatively scarce in the repertoire. This process is not affected in lupus; accordingly, the frequency of self-reactive T cells in peripheral blood is not higher in humans and mice with lupus than in their healthy counterparts.

Self-reactive B cells are eliminated from the repertoire through deletion, anergy, or receptor editing, at two checkpoints during a process that is less stringent than T-cell negative selection. The first checkpoint occurs in the bone marrow and the second one in the periphery, before the cell becomes an immunocompetent mature naïve B cell. It has been estimated that in healthy humans this decreases the frequency of self-reactive B cells from 50%–75% to 5%–20%. In lupus patients, the second checkpoint is abnormally lax, and therefore the frequency of self-reactive mature B cells is significantly higher than in controls. The fact that in healthy individuals the loss of tolerance toward self-antigens is rather rare, even in the presence of a relatively high abundance of self-reactive B cells (∼5%–20%), indicates that CD4 ⁺ T cells play an essential role in safeguarding self-tolerance, and suggests that defects in T-cell regulation may allow the autoimmune response to occur in patients with SLE. The characteristics of the autoantibodies found in patients with SLE further support the notion that CD4 help is involved in their generation: antibodies are mostly of high affinity, class switched, and carrying somatic mutations in the V _H regions.

Only a fraction of autoreactive CD4 T cells cloned from mice with lupus has the ability to promote the production of pathogenic antiDNA antibodies and accelerate nephritis when transferred into lupus-prone mice. These CD4 T cells respond to nucleosomal antigens, in particular to peptides derived from histones. Thus self-reactive B cells able to recognize DNA may endocytose complexes of nucleic acid and associated proteins and receive help from CD4 T cells that recognize peptides derived from the protein part of the complex (e.g., histone) ( Fig. 15.1 ).

Follicular helper T cells (T _FH ; CD4 ⁺ CXCR5 ^hi PD-1 ^hi ) represent the CD4 ⁺ helper subset specialized in providing help to B cells within germinal centers (GCs). Naïve CD4 ⁺ T cells differentiate to T _FH when their priming occurs in the presence of IL-6, IL-21, and costimulation through inducible T cell costimulator (ICOS). This process is regulated by the balance of two transcription factors: Bcl-6 (B-cell lymphoma 6) promotes their generation, whereas Blimp-1 (B lymphocyte-induced maturation protein 1) inhibits it. CXCR5 surface expression allows them to migrate into the B-cell follicles in response to CXCL13, where they promote B-cell growth, differentiation, class switching, and somatic hypermutation through IL-4, IL-10, IL-21, and CD40L.

Experiments in animal models have demonstrated that the expansion of T _FH is associated with the development of lupus-like autoimmunity, suggesting that the dysregulation of the GC can lead to tolerance failure. In agreement with these results, the deficiency of ICOS, required for the development of T _FH , has a protective role in MRL/ lpr lupus-prone mice. Moreover, it has been reported that a CD4 ⁺ cell subset that resembles T _FH is expanded in the peripheral blood of patients with SLE, in particular during active disease, suggesting an association between T _FH numbers and lupus activity. Intriguingly, T _FH cells have also been found in kidneys of patients with SLE in close association to B cells, suggesting that their pathogenic capacity extends to nonlymphoid organs.