T cell help in the autoreactive germinal center

Abstract

The germinal center serves as a site of B cell selection and affinity maturation, critical processes for productive adaptive immunity. In autoimmune disease tolerance is broken in the germinal center reaction, leading to production of autoreactive B cells that may propagate disease. Follicular T cells are crucial regulators of this process, providing signals necessary for B cell survival in the germinal center. Here, we review the emerging roles of follicular T cells in the autoreactive germinal center. Recent advances in immunological techniques have allowed study of the gene expression profiles and repertoire of follicular T cells at unprecedented resolution. These studies provide insight into the potential role follicular T cells play in preventing or facilitating germinal center loss of tolerance. Improved understanding of the mechanisms of T cell help in autoreactive germinal centers provides novel therapeutic targets for diseases of germinal center dysfunction.

Figure 1.. Failures in clonal redemption lead to loss of tolerance.

Autoreactive B cells normally undergo SHM to lose self-reactivity in a process termed clonal redemption. Anergic B cells that have escaped central tolerance are recruited into the GC of SLOs and mutate away from self to receive T cell help, which facilitates CSR and LLPC development. This process is regulated by checkpoints such as limited antigen-specific TFH cells, limited antigen availability on FDCs, co-stimulation provided by TFH cells, and TFR cells. We propose that in autoantibody disease an autoreactive B cell clone escapes clonal redemption due to failures of these checkpoints, triggering TFH dysfunction and epitope spreading towards autoantigens. SHM, somatic hypermutation; CSR, class switch recombination; GC, germinal center; TFH, follicular helper T cell; TFR, follicular regulatory T cell; FDC, follicular dendritic cell; LLPC, long lived plasma cell; SLO, secondary lymphoid organ; ASC, antibody secreting cell.

Figure 2.. Hallmarks of TFH dysregulation in autoimmune disease.

TFH cells isolated from mice and humans with autoimmune disease exhibit transcriptional and functional changes. We propose that loss of GC tolerance is due to TFH dysregulation, albeit through various mechanisms of dysfunction. TFH cells might permit or promote autoreactive B cell development due to dysregulated transcription factor expression, cytokine and chemokine profiles, co-stimulation, metabolism, exhaustion, and trafficking. GC, germinal center; TFH, follicular helper T cell.

Figure 3.. Bystander activation and cross-reactivity of the TFH repertoire.

Repertoire wide analyses have revealed that both immunization and autoimmune disease result in polyclonal responses of TFH and TFR cells. Computational prediction of antigen specificities also suggests overlap between autoimmune and foreign antigen elicited follicular T cell repertoire specificities. We propose that the cross reactivity of the TCR is responsible for non-specific bystander activation, which allows for provision of T cell help to autoreactive B cells, particularly in situations of chronic GC or extrafollicular B cell activation. GC, germinal center; TFH, follicular helper T cell; TFR, follicular regulatory T cell.

Figure 4.. Extrafollicular sites of autoantibody production.

T cell help to autoreactive B cells may be provided by cells other than follicular T cells and at locations other than GCs. TPH, cTFH, TRH, TH17, and CD8 T cells exhibit dysregulation in autoantibody disease and might also contribute to loss of GC tolerance. Autoantibodies might also originate from SLO EF and TLS, which might serve as sites of loss of tolerance or epitope spreading, respectively. GC, germinal center; TPH, peripheral helper T cell; cTFH, circulating follicular helper T cell; TRH, resident helper T cell; EF, extrafollicular foci; TLS, tertiary lymphoid structure; FO, follicle; ASC, antibody secreting cell; SLO, secondary lymphoid organ.

Figure 5.. Dysregulated GCs in autoimmune disease, cancer, and COVID-19.

Mechanisms of dysfunctional T cell help in autoantibody disease are applicable to other forms of GC dysfunction. (A) Molecular mimicry is an etiology of MS and might be driven by the cross reactivity of the TFH repertoire. (B) In contrast, epitope spreading might enhance anti-tumor immune responses, although might also exacerbate irAE following immune checkpoint blockade in cancer. (C) T cell independent neutralizing antibodies against SARS-CoV-2 are made in COVID-19, although EF and pathogenic autoantibodies are also observed in severe COVID-19. GC, germinal center; TFH, follicular helper T cell; EBV, Epstein-Barr virus; MS, multiple sclerosis; irAE, immune related adverse event; EF, extrafollicular foci; MIS-C, multisystem inflammatory syndrome in children; PASC, post-acute sequelae of COVID-19.