Germinal Center B Cell Depletion Diminishes CD4+ Follicular T Helper Cells in Autoimmune Mice
et al. (2014) Germinal Center B Cell Depletion Diminishes CD4+ Follicular T Helper Cells in
Autoimmune Mice. PLoS ONE 9(8): e102791. doi:10.1371/journal.pone.0102791
Isharat Yusuf 0
Jessica Stern 0
Tom M. McCaughtry 0
Sandra Gallagher 0
Hong Sun 0
Changshou Gao 0
Thomas Tedder 0
Gianluca Carlesso 0
Laura Carter 0
Ronald Herbst 0
Yue Wang 0
Yolande Richard, COCHIN INSTITUTE, Institut National de la Sante et de la Recherche Medicale, France
0 1 Department of Respiratory, Inflammation and Autoimmunity Research, MedImmune LLC, Gaithersburg, Maryland, United States of America, 2 Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, Maryland, United States of America, 3 Department of Immunology, Duke University Medical Center , Durham, North Carolina , United States of America
Background: Continuous support from follicular CD4+ T helper (Tfh) cells drives germinal center (GC) responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization. Methods and Finding: Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model. Conclusion: These data suggest that mature Tfh cells require signals from GC B cells to sustain their optimal numbers and function in both autoimmune and immunization models. Thus, immunotherapies targeting B cells in autoimmune disease may affect pathogenic Tfh cells.
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Competing Interests: The following authors are or were full-time employees of MedImmune: IY, JS, TM, SG, GC, RH, LC, and YW. TT is a paid consultant and
shareholder for Angelica Therapeutics. The authors confirm that MedImmune provided support in the form of salaries for authors [IY, JS, TM, SG, GC, RH, LC, YW],
but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of
these authors are articulated in the author contributions section. An affiliation to the commercial funders of this research study (MedImmune) does not alter the
authors adherence to all PLOS ONE policies on sharing data and materials.
Germinal centers (GC) are the prominent places for generation
of self-reactive B cells in autoimmune diseases and GC responses
are driven mainly by CD4+ T-helper cells confined within B cell
follicles called T follicular helper (Tfh) cells [111]. Throughout
the course of GC responses, Tfh cells persistently provide an array
of signals to GC B cells, such as CD40 ligand (CD40L), interleukin
(IL)-21 and IL-4, which in combination support GC B cell
proliferation, somatic hypermutation, immunoglobulin class
switching, and eventual differentiation into memory B cells and
plasma cells [4,1214]. Increased numbers of Tfh cells and/or
dysregulated Tfh function contribute to the development of
autoimmune phenotype in multiple autoimmune mouse models
and expansion of Tfh-like cells have been reported in the
peripheral blood from patients with Systemic lupus erythematosus
(SLE), primary Sjogrens syndrome, rheumatoid arthritis and
myasthenia gravis patients [2,3,1532]. Together, these findings
suggest that Tfh cells are promising therapeutic targets in
autoimmune patients.
Recent studies using immunization or infection models have
shed light on the pathways leading to the development of Tfh cells
in these models [4,33]. First, Tfh cells require Bcl-6 for their
development and proper function [3436]. Second, antigen
presenting cells (APCs) play important roles for Tfh development,
with dendritic cells and B cells working in tandem at different
stages of Tfh differentiation [3739]. Third, several signaling
pathways including CD28, ICOS, and SAP have been shown to
be critical for Tfh differentiation [4]. Finally, in an Ovalbumin
immunization model, the maintenance of the Tfh cells throughout
the course of GC responses was dependent on persistent antigen
presentation and ICOS-ICOSL signals provided by GC B cells
[40]. However, it was also reported (...truncated)