T Follicular Helper Cell Pathway Follicular References: Dendritic Cell 1

T Follicular Helper Cell Pathway Follicular References: Dendritic Cell 1. Nurieva, R. et al. 2008. Immunity 29:138-149. 2. King, C. et al. 2007. Annu. Rev. Immunol. 26:741-766. Th2 Cell CXCL13 belongs to the CXC family of chemokines and is also known as B 3. Vinuesa, C.G. et al. 2005. Nature 5:853-865. Th1 Cell CXCR5 Lymphocyte Chemoattractant (BCL). CXCL13 is essential for the organization 4. Kim, HJ. et al. 2010. Nature 467:328. IL-4 of CXCR5-expressing B cells and Tfh cells within follicles of lymphoid tissues. TNF IL-13 STAT6 GATA3 CCR3 IFN-g T-bet IgM CCR4 CCR8 MHCII Plasma Cell Lymphoid Tissue CXCR3 B Cell Class Switch B Cell BCR IL-21R IL-12 CXCL13 IL-4 CXCR5 IL-10 Negative SLAM Feedback CD40 MHCII ICOSL ICOS Ligand-ICOS interaction is required B7 OX40L IgE ICOSL IL-27 CD40L for the development of Tfh cells. ICOS IL-27R TCR (inducible costimulator) is the third Activated T Cell ICOS CD28 Naïve T Cell Primed T Cell member of the CD28/CTLA-4 family. OX40 CD4 CXCR5 IgG1 TCR/CD3 ICOS STAT3 SLAM IL-6 is a cytokine with both pro- inflammatory and anti-inflammatory Bcl-6 IL-6R IgG2a/IgG3 IL-21 properties. It is an important mediator of SAP fever, immune responses to acute injury, CD28 TCR CD69 CXCR5 IL-6ST CCR7 and resistance to some bacteria. As an anti- CD28 (CD130) CCL19 CXCR5 CD84, Ly9 inflammatory cytokine, it inhibits TNF-a and IgG2b IL-21R MHCII B7-1 IL-6 IL-1, while it activates IL-1ra and IL-10. IL-6 is TGF-b required for the generation of Tfh cells. B7-2 IL-6 CXCL13 IL-21 IL-23 TGF-b Perforin

TGF-b CXCR5 ICOSL IL-4 IgA Dendritic Cell Bcl-6 GATA3 CD29 CD8 Treg SMAD Treg CD49d TCR Th17 Cell Th2 STAT3 Th17/Treg IL-22 CCR4 RORγt CD25 IL-17 CCR6 TGF- FOXP3 Follicular RORα b CD8 Dendritic Cell CD44 CD8 Tregs are important in maintaining self tolerance by limiting the functions GITR Follicular Stromal Cell CD122 of T follicular helper (Tfh) cells that drive antibody production from B cells. Kim and colleagues characterized this mechanism as a means to inhibit autoimmune disease, thereby maintaining self tolerance in mice. Unlike CD4+ Tregs, CD8+ CXCR5, now designated as CD185, is a seven transmembrane receptor IL-21 is a cytokine structurally similar to IL-2 and IL-15. It is produced by Tregs do not express FoxP3 or CTLA-4, and do not have diminishing levels of for the chemokine CXCL13 (BLC). CXCR5 is expressed on B cells. While it is activated T cells, and it induces proliferation of T and B cells. It also induces CD127. In addition, the mechanism of inhibition differs significantly between the transiently expressed upon activation of T cells, CXCR5 is stably expressed cytolytic activity of NK cells. IL-21 in the absence of TGF-b initiates Tfh cell two regular subtypes, as CD8+ Tregs require perforin for their inhibitory activity. on Tfh cells. differentiation. CD8 Tregs can be characterized by surface expression of CXCR5 and ICOSL.

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