CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles

Abstract

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.

Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8+CellsIn Vivo

“…Additional evidence that follicular CD8 ϩ T cells suppress viral replication was presented in two recently published studies (64,65). Follicular CXCR5 ϩ lymphocytic choriomeningitis virus (LCMV)-specific CD8 ϩ T cells were shown to control LCMV infection of T FH cells and to reduce viral loads significantly better than CXCR5 Ϫ CD8 ϩ T cells adoptively transferred to LCMVinfected mice (64,65).…”

“…Follicular CXCR5 ϩ lymphocytic choriomeningitis virus (LCMV)-specific CD8 ϩ T cells were shown to control LCMV infection of T FH cells and to reduce viral loads significantly better than CXCR5 Ϫ CD8 ϩ T cells adoptively transferred to LCMVinfected mice (64,65). In addition, and importantly, HIV-specific CXCR5 ϩ CD8 ϩ T cell levels in blood inversely correlated with viral loads for untreated chronically HIV-infected patients (64).…”

The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles

“…Although it remains possible that other mechanisms, such as T cell exhaustion, may also play a role, our data are in line with other recent reports of IL-15-induced migration of memory T cells out of the peripheral blood into tissue. 18 It is well established that CD8 1 T cells are predominantly excluded from B-cell follicles, [1][2][3][4]19 and that during HIV and SIV infection, these lymph node follicles become sanctuary sites for viral replication by avoiding antiviral CD8 1 T cells. 5 In the absence of virus-specific CD8 1 T-cell surveillance, B-cell follicles are thus established as long-lasting sites of the HIV and SIV viral reservoir.…”

“…[1][2][3][4] Viral pathogens like HIV and Epstein-Barr virus exploit this anatomic segregation to establish persistent reservoirs in CD4 1 follicular helper T (T FH ) cells and B cells, respectively, residing within the B-cell follicle. In HIV elite controllers and antiretroviral therapy (ART)-treated patients, T FH cells are the major source of persistent HIV.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…GC Tfh cells are not only highly activated cells that are good targets for HIV‐1 infection but are also located in close proximity to FDCs, which are an important reservoir of infectious virus and can readily transmit infection to Tfh cells 180, 181, 182, 183. Virus replication in GC Tfh cells may also be facilitated by the limited ability of antiviral CD8 + T cells to enter B‐cell follicles,168, 171, 175, 179, 184 although recent studies in the lymphocytic choriomeningitis virus (LCMV) mouse model show that persisting virus can be cleared from Tfh cells and B cells by a CXCR5 +  CD8 + T‐cell population that is able to enter B‐cell follicles,185, 186, 187 raising the intriguing prospect that if an analogous antiviral CD8 + T‐cell population expressing sufficiently high levels of CXCR5 could be induced in humans, this may enable targeting of Tfh cells that harbor persistent HIV‐1 such as the latent pool.…”