Dysregulation of T Follicular Helper Cells in Lupus

Abstract

Although multiple and overlapping mechanisms are ultimately responsible for the immunopathology observed in patients with systemic lupus erythematosus, autoreactive Abs secreted by autoreactive plasma cells (PCs) are considered to play a critical role in disease progression and immunopathology. Given that PCs derive from the germinal centers (GC), long-term dysregulated GC reactions are often associated with the development of spontaneous autoantibody responses and immunopathology in systemic lupus erythematosus patients. In this review, we summarize the emerging evidence concerning the roles of T follicular helper cells in regulating pathogenic GC and autoreactive PC responses in lupus.

Figure 1.. Classical Tfh cells in the light zone of a spontaneous GC in BXD2 mice.

Expression of CXCR5 on both Tfhs and B cells assist their co-localization near CXCL13 expressing CD35⁺ FDCs in the light zone of the GC. The representative PNA⁺ GC (blue) GC was derived from the spleen of a BXD2 mouse. The structure of this spontaneous GC is similar to immunized GCs in which CXCR5⁺ (red) CD4⁺ (green) Tfh cells (yellow) are polarized to the light zone (LZ) end. In contrast, CXCR5⁻ cells are polarized to the dark zone (DZ) end (44) (Ding et al, J Immunol, 2013).

Figure 2.. Autoreactive GC development require cooperation between multiple Tfh subpopulations.

(A). Confocal image of a spontaneous GCs result from interactions of CD4⁺ Tfh B cells that express Bcl6 and a separate population of CD4 T cells that express IL-17 in the LZ of the GC. The representative BCL6⁺ GC (red) is derived from the spleen of a BXD2 mouse. The GC is simultaneously stained with an anti-mIL-17 (white) and an anti-mCD4 (green) to illustrate the distribution of Tfh-IL-17⁺ cells in the GC (objective lens 20×). (B) In the spleen, development of mixed populations of Tfh occur at the late naïve stage (CD62L⁺CD44⁺, Population C) when there is high expression of IL-21, IL-17, CXCR5 and ICOS. This population has undergone approximately 4 cell divisions as indicated by a quantitative real-time PCR-based TREC assay(148), and expresses the highest levels of IL-21 or IL-17 as analyzed by intracellular flow cytometry(44).

Fig 3.. Accessory Tfh cells in a spontaneous pathologic autoreactive GC.

Diagram of spontaneous GCs result from interactions of T cells with B cells and FDCs at the T-B border similar to those associated with induced GCs except that the affinity of the T-cell interaction is lower and autoantigen abundance may be higher. Autoreactive GCs that arise spontaneously and is enabled by incorporation of mixed populations of Tfh cells. The primary pathogenic Tfh are development of Tfh-IL17 from RORᵧt expressing Tfhs or Tfh-IFNɣ from Tbet. Such accessory Tfh cells in the GCs can lead to increased expression and engagement of co-stimulatory molecule interactions, such as CD28-CD86, ICOS-ICOS-ligand, or CD40 ligand-CD40.