Follicular helper T cells are required for systemic autoimmunity

By M. Linterman, R. Rigby, Raphael. K. Wong, Di Yu, R. Brink, Jennifer L Cannons, P. Schwartzberg, M. Cook, G. Walters, Carola G. Vinuesa. Journal of Experimental Medicine, 2009

614 citations recorded by the source corpus.

Production of high-affinity pathogenic autoantibodies appears to be central to the pathogenesis of lupus. Because normal high-affinity antibodies arise from germinal centers (GCs), aberrant selection of GC B cells, caused by either failure of negative selection or enhanced positive selection by follicular helper T (TFH) cells, is a plausible explanation for these autoantibodies. Mice homozygous for the san allele of Roquin, which encodes a RING-type ubiquitin ligase, develop GCs in the absence of foreign antigen, excessive TFH cell numbers, and features of lupus. We postulated a positive selection defect in GCs to account for autoantibodies. We first demonstrate that autoimmunity in Roquinsan/san (sanroque) mice is GC dependent: deletion of one allele of Bcl6 specifically reduces the number of GC cells, ameliorating pathology. We show that Roquinsan acts autonomously to cause accumulation of TFH cells. Introduction of a null allele of the signaling lymphocyte activation molecule family adaptor Sap into the sanroque background resulted in a substantial and selective reduction in sanroque TFH cells, and abrogated formation of GCs, autoantibody formation, and renal pathology. In contrast, adoptive transfer of sanroque TFH cells led to spontaneous GC formation. These findings identify TFH dysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity.

Subfields: Immunology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/893b0263bf164f1140bb6a4750076c478a1ff0f5

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Shane Crotty
2. Jacques Banchereau
3. M. Smyth
4. V. Pascual
5. D. Godfrey
6. Carola G. Vinuesa
7. Di Yu
8. K. Palucka

Citations in the corpus

• IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses (2010, background): “We have recently shown that Bcl-6 acts in a gene dose–dependent manner: halving the gene dose of Bcl6 reduced GCs after SRBC immunization by nearly 50% (Linterman et al., 2009b).”
• Foxp3+ follicular regulatory T cells control T follicular helper cells and the germinal center response (2011, background): “Limiting the numbers of T FH cells within germinal centers is critical to prevent the emergence of autoantibodie”
• IL-21 regulates germinal center B cell differentiation and proliferation through a B cell–intrinsic mechanism (2010, background): “, 2008), whereas other data suggest a less universal association (Linterman et al., 2009).”
• T follicular helper cell biology: A decade of discovery and diseases (2019, background): “A clear causal role for Tfh cells in disease progression in mice has been shown for autoantibody-associated autoimmunity in the sanroque SLE model (Linterman et al., 2009) and related models (Gensous et al., 2018).”
• New insights into the regulation of T cells by γc family cytokines (2009, neutral): “Although the differentiation of T FH cells during a normal T cell-dependent antibody response requires IL-21 production, the excessive differentiation of T FH cells that accompanies systemic autoimmunity in sanroque mice is independent of IL-21, which indicates that there are alternative mechani”
• Human Blood CXCR5+CD4+ T Cells Are Counterparts of T Follicular Cells and Contain Specific Subsets that Differentially Support Antibody Secretion (2011, background): “Furthermore, although several mouse studies show that over- representation of Tfh cells is associated with the development of systemic autoimmunity (Linterman et al., 2009; Subramanian et al., 2006; Vinuesa et al., 2005), their association with human autoimmune diseases remains largely unknown.”
• The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. (2009, neutral): “For these experiments, CD28-deficient fetal liver cells were chosen as a source for T cells unable to differentiate into Tfh cells (Linterman et al., 2009) and a source of B cells competent to differentiate into GC B cells.”