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.
Subject(s)
Arenaviridae Infections/immunology , B-Lymphocytes/immunology , Epstein-Barr Virus Infections/immunology , HIV/immunology , Lymphocytic choriomeningitis virus/immunology , T-Lymphocytes, Cytotoxic/immunology , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation , Cells, Cultured , Gene Expression Regulation , Germinal Center/pathology , Germinal Center/virology , Hepatocyte Nuclear Factor 1-alpha/genetics , Hepatocyte Nuclear Factor 1-alpha/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Positive Regulatory Domain I-Binding Factor 1 , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism , Receptors, CXCR5/genetics , Receptors, CXCR5/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Human immunodeficiency virus (HIV) infects millions of people worldwide, and new cases continue to emerge. Once infected, the virus cannot be cleared by the immune system and causes acquired immunodeficiency syndrome. Combination antiretroviral therapeutic regimen effectively suppresses viral replication and halts disease progression. The treatment, however, does not eliminate the virus-infected cells, and interruption of treatment inevitably leads to viral rebound. The rebound virus originates from a group of virus-infected cells referred to as the cellular reservoir of HIV. Identifying and eliminating the HIV reservoir will prevent viral rebound and cure HIV infection. In this review, we focus on a recently discovered HIV reservoir in a subset of CD4+ T cells called the follicular helper T (TFH) cells. We describe the potential mechanisms for the emergence of reservoir in TFH cells, and the strategies to target and eliminate this viral reservoir.