Taken together, a number of potential mechanisms likely contribute to the depletion of Tfh cells in some subjects and further studies are required to address this question in greater detail. Numerous studies have shown that HIV infection is associated with B cell abnormalities such as hypergammaglobulinemia, polyclonal B cell activation79,80and B cell driven lymphadenopathy8183. infection. Keywords:simian, HIV, SIV, IL-21, Tfh, B cells == Introduction == Nave CD4 T cells can differentiate into, distinct lineages that can be identified based on their unique cytokine signature and expression of transcription factors that drive their differentiation; T-helper-1 (Th1) cells express IFN and Tbet, while T-helper-2 (Th2) cells express IL-4 and Gata3, and T-helper-17 (Th17) cells that express IL-17 and RORt1. Recent studies have identified a novel class of CD4 T helper cells called the T-follicular helper cells (Tfh) that preferentially express IL-21 and the transcription factor Bcl6. Tfh cells have also been shown to secrete other cytokines such as IFN, IL-4 and IL-171,2. Initial evidence for the existence of Tfh cells came from studies that characterized the expression of CXCR5 on memory CD4+ T cells that that were found to be associated with B cells in the Germinal Center (GC) follicles36. Tfh cells are a primary source of IL-21 in the GC and provide critical help to GC B cells. Mice lacking IL-21 or IL-21R have low numbers of IgG switched B cells7suggesting that IL-21 plays a crucial role in Ig class switching in the LN follicles8,9. Likewise, IL-21 has been shown to play an important role in B cell differentiation to plasma cells10,11, and essential for the survival of memory B cells in the GC10,12. Paradoxically, IL-21 can have a proapoptotic effect on B MG-132 cells13under certain conditions such as when they receive co-stimulatory signals via Toll like receptors TLR)-4 and -914. This effect appears to be caspase dependent10. Tfh cells, unlike other T helper lineages, express high levels of Bcl6, a transcriptional repressor initially discovered in B cell lymphomas15and a negative regulator of transcription for a number of proteins which plays a critical role in Tfh differentiation16,17. Additionally, Tfh cells MG-132 have been shown to express a number of co-stimulatory molecules such as ICOS, PD-1, CD40L that interact with their cognate ligands on B cells in the GC (Fig. 1) and a number of other proteins such as SAP, OX40, CD30L and BTLA2,18. The exact role some of these proteins may play in Tfh mediated help is still under investigation. Interestingly, Tfh cells display reduced expression of CCR7 (the receptor for CCL19 and CCL21 in T cell zones) that likely MG-132 allows these cells to home to the border of the T and B cell zones where they mediate their function19. == Figure 1. == T follicular helper cell and B cell interaction in the lymph node A number of recent studies have identified a class of CD4 T cells in blood, based on high CXCR5 expression, that exhibit functions similar to Tfh cells found in the lymph nodes. They secrete high levels of IL-21 and are specialized for providing help to B cells20. Locci et al21described a subset of PD-1+CXCR3CXCR5+CD4+memory T Cells in the periphery that had a transcriptional profile similar to Tfh cells in the LN and Boswell et al22reported that CCR7hiCXCR5hiCCR6hiPD-1hiCD4 T cells in peripheral blood were highly specialized in secreting IL-21 and providing help to B cells. Pallikkuth et al23showed that peripheral Tfh cells expressed CXCR5 and displayed CTSD a central memory phenotype and play a critical helper function in generating vaccine responses. == Tfh Differentiation and Bcl-6 Expression == Early events in Tfh differentiation begin with recognition of antigen on DC by CD4 T cells leading to.