Poster Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Primary immunodeficiencies reveal quantitative and qualitative consequences of single gene mutations on the generation and function of human T follicular helper cells (#216)

Cindy S Ma 1 , Natalie Wong 1 , Danielle T Avery 1 , James Torpy 1 , Geetha Rao 1 , Elissa K Deenick 1 , Matthew C Cook 2 , Steven M Holland 3 , Jean-Laurent Casanova 4 , Gulbu Uzel 3 , Stuart G Tangye 1
  1. Garvan Institute, Darlinghurst, NSW, Australia
  2. The Canberra Hospital, Canberra, ACT
  3. NIAID, National Institutes of Health, Bethesda, MD, USA
  4. Rockefeller University, New York, USA

T follicular helper (Tfh) cells are a specialised population of CD4+ T cells that provide help to B cells for their differentiation into memory and plasma cells, which underlie long-lived humoral immunity. Tfh cells express high levels of the chemokine receptor CXCR5, the surface receptors PD-1 and ICOS, together with the transcriptional repressor Bcl-6 and the cytokine IL-21. Tfh generation is strictly controlled, because aberrant Tfh formation has been associated with several immunological diseases. Thus, excessive Tfh cell numbers have been implicated in pathogenesis of autoantibody-mediated autoimmune diseases, while a paucity of Tfh cells underlies impaired humoral immunity in primary immunodeficiencies.

 Studies in mice have revealed many of the requirements for Tfh generation, including cytokines (IL-6, IL-21, IL-27), surface receptors (CD40L, ICOS, SLAM-family) and associated signaling pathways (STAT1, STAT3, SAP), and various transcriptional regulators (Bcl-6, IRF4, BATF, MAF, Ascl2). However, to develop approaches of targeting Tfh cells to treat human immunological dyscrasias, the molecular requirements for Tfh formation in humans need to be determined.

To achieve this we assessed the consequences of monogenic mutations that cause primary immunodeficiencies on human Tfh cells. Our analyses revealed reductions in frequencies of circulating Tfh cells in individuals with loss-of function (LOF) mutations in STAT3, CD40LG, NEMO, BTK and ICOS. Furthermore, STAT3LOF and STAT1 gain of function (GOF) mutations skewed Tfh cells towards a Th1 effector subset at the expense of the B-cell helper subset, and also resulted in dysregulated expression of PD-1. These defects compromise the ability of STAT3 LOF and STAT1GOF Tfh cells to provide optimal help to B cells.

 This study reveals the power of examining “Experiments of Nature” to delineate signaling pathways required for human lymphocyte differentiation and effector function, and provide a framework to identify molecules to target to modulate these processes in the setting of human disease.