BCL6 represses antiviral resistance in follicular T helper cells

Abstract

Follicular Th (Tfh) cells are a distinct subset of Th cells that help B cells produce class-switched antibodies. Studies have demonstrated that Tfh cells are highly prone to HIV infection and replication. However, the molecular mechanisms underlying this phenomenon are largely unclear. Here, we show that murine and human Tfh cells have diminished constitutive expression of IFN-stimulated genes (ISGs) inclusive of antiviral resistance factor MX dynamin-like GTPase 2 (MX2) and IFN-induced transmembrane 3 (IFITM3) compared with non-Tfh cells. A lower antiviral resistance in Tfh was consistent with a higher susceptibility to retroviral infections. Mechanistically, we found that BCL6, a master regulator of Tfh cell development, binds to ISG loci and inhibits the expression of MX2 and IFITM3 in Tfh cells. We demonstrate further that inhibition of the BCL6 BR-C, ttk, and bab (BTB) domain function increases the expression of ISGs and suppresses HIV infection and replication in Tfh cells. Our data reveal a regulatory role of BCL6 in inhibiting antiviral resistance factors in Tfh cells, thereby promoting the susceptibility Tfh cells to viral infections. Our results indicate that the modulation of BCL6 function in Tfh cells could be a potential strategy to enhance Tfh cell resistance to retroviral infections and potentially decrease cellular reservoirs of HIV infection.

Expression of the miR-302/367 microRNA cluster is regulated by a conserved long non-coding host gene

“…It is a key regulator gene in multiple myeloma [41,42]. BCL-6 has also been reported to be an antiviral resistance repressor in follicular T helper cells [43]. Hyper methylated In Cancer 1 (HIC1) is a transcriptional repressor that acts as a tumor suppressor and frequently is inactivated by epigenetic silencing.…”

The IFITM protein family in adaptive immunity

“…The IFITM1-3 genes are expressed in human lymphocytes, and IFITM1 is expressed at their cell surface, where it has been shown to associate with receptor signalling complexes. 12,[31][32][33] The IFITM family in T-cell differentiation and function…”

“…7,8 Interestingly, IFITM3 is also constitutively expressed in tissue-resident T cells in lung and airways, and also spleen, skin and brain, suggesting that it promotes their survival at these sites of potential viral infection. 8,12,13,37,53,69 Hence, several in vivo and in vitro studies have demonstrated the importance of IFITM3 in immunity to viral infection, by enhancing survival and viral resistance of immune effector populations, but these studies did not demonstrate an additional direct function of the IFITM proteins in the immune function of T cells or dendritic cells.…”

“…Several studies have shown that IFITM proteins enhance immunity to viral disease by inhibiting viral infection of immune effector cells, thereby enhancing their survival and ability to mount an effective immune response, 7,8,12,38 but the way in which IFITM proteins prevent viral infection is unclear and seems dependent on the cell type and the particular IFITM family member and virus interaction, with experimental evidence supporting many possible mechanisms, including inhibition of viral entry, fusion, transcription and translation. 3 Our recent study highlighted a virus-independent T-cell-intrinsic function for IFITM proteins in Th differentiation 13 and although the mechanism for their T-cell-intrinsic influence on Th differentiation is also unknown and requires investigation, several possibilities arise by extrapolation from the virusrestriction studies and from their cellular localization and expression patterns.…”

“…[4][5][6][7] However, IFITM expression can be regulated independently of interferon signalling. 7,8 Ifitm genes are targets of transcriptional repression by Bcl6, and have been shown to be targets of Wnt/b-catenin and Hedgehog (Hh) signal transduction [9][10][11][12] ; and in murine T cells IFITM2 and IFITM3 expression is regulated by T-cell receptor (TCR) signal transduction. 7,9,13 In humans, five IFITM genes have been identified, which are located on chromosome 11, whereas in mice there are seven Ifitm genes, six of which are located on chromosome 7, and one on chromosome 16 (illustrated in Fig.…”