IL-21 reporter mouse shines more light on follicular helpers

Follicular helpers are the special population of CD4 T cells that localize to germinal centers and are involved in enhancing the humoral response. They are distinguishable from other CD4 T cell subsets by their joint expression of CXCR5, ICOS, PD-1 and the transcription factor Bcl-6 as well as the capacity to secrete IL-21 cytokine. The recent paper describes a novel model to study the biology of TFH – the IL-21 reporter mouse. Such mouse has a GFP encoding cassette knocked-in into IL-21 locus to create the animal that expresses simultaneously IL-21 and GFP. IL-21 is not a cytokine characteristic exclusively for TFH but in conditions applied by this study the GFP presence in secondary lymphoid organs is restricted to activated CD4 T cells that are positive for CXCR5 and PD-1 thus being follicular helpers according to the accepted definition. The ability to track TFH population in vivo allows answering questions concerning their fate after the primary immune response is over and germinal centers undergo resolution.

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There are two main contributions that this paper adds to the existing knowledge of TFH. First, it dissects follicular helpers into IL-21 secreting and IL-21 negative populations and characterizes both subsets. Second, it analyzes the ability of TFH to form the memory compartment and participate in recall responses. In order to track IL-21 secreting cells among TFH authors follow general follicular helper population (defined as CD4+CD44+CD62LCXCR5+PD-1+cells) after the immunization with NP-KLH (a T cell-dependent antigen). They discover that GFP-positive cells constitute a stable proportion of TFH (~30-40%) at every time points during the course of primary response. Both IL-21 secreting (GFP+) and IL-21 negative (GFP) subpopulations are mostly equivalent in terms of transcription factors (Bcl-6, IRF4, Blimp-1, T-bet and GATA3 tested) and cytokine expression (IFN-γ, IL-4 and IL-10 examined), proliferation and functional abilities (NP-specific GC B cell response analyzed). The only difference between two subsets was an increase in transcripts encoding T-bet, IFN-γ and IL-10 among GFPcells.

The potential of TFH to participate in recall responses is tested by adoptive transfer approach. Follicular helpers generated in the course of immune response to influenza virus (flu infection similarly to NP-KLH immunization leads to the formation of GFP+ and GFP– subsets of TFH) were injected into congenic recipients challenged subsequently with the same virus. It is observed that antigen-experienced  TFH have the ability to expand on re-stimulation in vivo. Transferred follicular helpers are then analyzed by their surface marker expression and cytokine profile.  In secondary lymphoid organs TFH have a definite propensity to continue as TFH. However, at effector sites (lungs) the vast majority of former follicular helpers become conventional effectors CD4 T cells. Follicular helpers retain also the substantial ability to release cytokines on antigen re-exposure. It is interesting to know that TFH have some plasticity and may end up doing different tasks after germinal centers of primary immune response are disbanded.

Lüthje, K., Kallies, A., Shimohakamada, Y., Belz, G., Light, A., Tarlinton, D., & Nutt, S. (2012). The development and fate of follicular helper T cells defined by an IL-21 reporter mouse Nature Immunology, 13 (5), 491-498 DOI: 10.1038/ni.2261

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