T follicular helper (Tfh) cells are heterogeneous and mainly characterized by expressing surface markers CXCR5, ICOS, and PD-1; cytokine IL-21; and transcription factor Bcl6. They are crucial for B-cell differentiation into long-lived plasma cells and high-affinity antibody production. T follicular regulatory (Tfr) cells were described to express markers of conventional T regulatory (Treg) cells and Tfh cells and were able to suppress Tfh-cell and B-cell responses. Evidence has revealed that the dysregulation of Tfh and Tfr cells is positively associated with the pathogenic processes of autoimmune diseases. Herein, we briefly introduce the phenotype, differentiation, and function of Tfh and Tfr cells, and review their potential roles in autoimmune diseases. In addition, we discuss perspectives to develop novel therapies targeting Tfh/Tfr balance.

T follicular helper cells and T follicular regulatory cells in autoimmune diseases

The interactions between T cells and B cells are essential for antibody responses and the development of autoimmune diseases. Recently, a distinct subset of T cells capable of helping B cells was established in synovial fluid, and they were termed peripheral helper T (Tph) cells. PD-1hiCXCR5−CD4+ Tph cells express high levels of CXCL13, which drives the formation of lymphoid aggregates and tertiary lymphoid structures, ultimately facilitating the local production of pathogenic autoantibodies. Tph and T follicular helper cells share some key features but can be distinguished by their surface markers, transcriptional regulation, and migration capability. We summarize recent findings on Tph cells in this review and provide a perspective on their potential roles in a range of autoimmune diseases. More clinical and in-depth mechanistic investigations of Tph cells may help to improve the understanding of pathogenesis and further provide novel therapeutic targets in autoimmune diseases.

/pdf/t-peripheral-helper-cells-in-autoimmune-diseases-what-do-we-3t5a8krr.pdf

T peripheral helper cells in autoimmune diseases: What do we know?

Recent technological progress has greatly advanced our understanding of human immunology. In particular, the discovery of human T follicular helper (Tfh) and T peripheral helper (Tph) cells has significantly advanced our understanding of human adaptive immune system. Tfh and Tph cells share similar molecular characteristics and both play critical roles in B cell differentiation and maturation. However, they differ in their functional properties, such as chemokine receptor expression and cytokine production. As a result, Tfh cells are mainly involved in B cell differentiation and maturation in germinal centres of secondary lymphoid tissues, while Tph cells are involved in B cell differentiation and tissue damage in peripheral inflammatory lesions. Importantly, the involvement of Tfh and Tph cells in the pathogenesis of rheumatic and musculoskeletal diseases has become clear. In rheumatoid arthritis and systemic lupus erythematosus, Tph cell infiltration is predominant in peripheral inflammatory lesions, whereas Tfh cell infiltration is predominant in the affected lesions of IgG4-related disease. Therefore, the contribution of Tfh and Tph cells to the development of rheumatic and musculoskeletal diseases varies depending on each disease. In this review, we provide an overview of human Tfh and Tph cells and summarise the latest findings on these novel T cell subsets in various rheumatic and musculoskeletal diseases.

T follicular helper cells and T peripheral helper cells in rheumatic and musculoskeletal diseases.

Shifting levels of E proteins and Id factors are pivotal in T cell commitment and differentiation, both in the thymus and in the periphery. Id2 and Id3 are two different factors that prevent E proteins from binding to their target gene cis-regulatory sequences and inducing gene expression. Although they use the same mechanism to suppress E protein activity, Id2 and Id3 play very different roles in T cell development and CD4 T cell differentiation. Id2 imposes an irreversible choice in early T cell precursors between innate and adaptive lineages, which can be thought of as a railway switch that directs T cells down one path or another. By contrast, Id3 acts in a transient fashion downstream of extracellular signals such as T cell receptor (TCR) signaling. TCR-dependent Id3 upregulation results in the dislodging of E proteins from their target sites while chromatin remodeling occurs. After the cessation of Id3 expression, E proteins can reassemble in the context of a new genomic landscape and molecular context that allows induction of different E protein target genes. To describe this mode of action, we have developed the “Clutch” model of differentiation. In this model, Id3 upregulation in response to TCR signaling acts as a clutch that stops E protein activity (“clutch in”) long enough to allow shifting of the genomic landscape into a different “gear”, resulting in accessibility to different E protein target genes once Id3 decreases (“clutch out”) and E proteins can form new complexes on the DNA. While TCR signal strength and cytokine signaling play a role in both peripheral and thymic lineage decisions, the remodeling of chromatin and E protein target genes appears to be more heavily influenced by the cytokine milieu in the periphery, whereas the outcome of Id3 activity during T cell development in the thymus appears to depend more on the TCR signal strength. Thus, while the Clutch model applies to both CD4 T cell differentiation and T cell developmental transitions within the thymus, changes in chromatin accessibility are modulated by biased inputs in these different environments. New emerging technologies should enable a better understanding of the molecular events that happen during these transitions, and how they fit into the gene regulatory networks that drive T cell development and differentiation.

/pdf/shifting-gears-id3-enables-recruitment-of-e-proteins-to-new-3u25vpcj.pdf

Shifting gears: Id3 enables recruitment of E proteins to new targets during T cell development and differentiation

Despite being some of the most anecdotally well-known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end-organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions.

Redox Pathogenesis in Rheumatic Diseases.

OBJECTIVE
Peripheral helper T (Tph) cells interact with B cells and promote immune responses at sites of ectopic lymphoid structures (ELSs). To assess the characteristics of Tph cells, we investigated the phenotype of T helper (Th) cells in patients with systemic lupus erythematosus (SLE) and the underlying competitive binding mechanisms using cytokines-mediated signal transducer and activator of transcription (STAT) factors.


METHODS
Peripheral blood mononuclear cells from SLE patients and healthy controls were analyzed for phenotype identifying. Serum cytokine levels were detected using Luminex assays. In vitro culture was performed to assess cytokine-induced conversion of phenotypes and transcriptional regulation using flow cytometry and PCR. Chromatin immunoprecipitation was used to evaluate STATs binding and histone modifications.


RESULTS
CXCR5-PD-1+Tph-like cells were increased in SLE patients and showed strong association with disease activity and renal involvement. Serum IFN-α levels were increased and associated with Tph frequency. IFN-α promoted the differentiation of IL-10-producing CXCR5-PD-1+Tph-like cells, increased the responsiveness of IL-2, and induced the conversion of Tfh-like cells to Tph-like cells. STAT5 gained advantage and bound to BCL6 locus at expense of STAT1, accompanied by suppression of H3K4me3. Finally, anti-IFNAR1 decreased the differentiation of Tph-like cells, thereby suppressing the generation of CD38highCD27highplasmablasts.


CONCLUSION
Tph cells might be crucial makers to effectively reflect disease activity level in SLE patients. The finding that synergy of IFN-α and IL-2 increases Tph cells through competitive transcriptional regulation, could be one of the mechanisms responsible for pathologic formation of ELSs and helpful for selection of individualized therapeutic approaches for SLE.

Competitive Binding of Transcription Factors Underlies Flexibility of T Peripheral Helper Cells and T Follicular Helper Cells in SLE.

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Competitive Binding of Transcription Factors Underlies Flexibility of T Peripheral Helper Cells and T Follicular Helper Cells in SLE.