Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection

During chronic viral infection, virus-specific CD8+ T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8+ T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8+ T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5+ CD8+ T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5− subset. Furthermore, we identified the Id2–E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5+ CD8+ T-cell subset, and its number was inversely correlated with viral load. The CXCR5+ subset showed greater therapeutic potential than the CXCR5− subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8+ T cells that has a pivotal role in the control of viral replication during chronic viral infection.

[1]  R. Zinkernagel,et al.  Induction and Exhaustion of Lymphocytic Choriomeningitis Virus–specific Cytotoxic T Lymphocytes Visualized Using Soluble Tetrameric Major Histocompatibility Complex Class I–Peptide Complexes , 1998, The Journal of experimental medicine.

[2]  M. McCarter,et al.  CTL Fail to Accumulate at Sites of HIV-1 Replication in Lymphoid Tissue12 , 2007, The Journal of Immunology.

[3]  D. Speiser,et al.  From T cell "exhaustion" to anti-cancer immunity. , 2016, Biochimica et biophysica acta.

[4]  A. Goldrath,et al.  Id2 reinforces TH1 cell differentiation and inhibits E2A to repress TFH cell differentiation , 2016, Nature Immunology.

[5]  Xiaolei Tang,et al.  Inhibition of follicular T helper cells by CD8+ Treg is essential for self tolerance , 2010, Nature.

[6]  E. Connick,et al.  TFH in HIV Latency and as Sources of Replication-Competent Virus. , 2016, Trends in microbiology.

[7]  J. Altman,et al.  Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function , 1998, The Journal of experimental medicine.

[8]  R. Thimme,et al.  Immune-surveillance through exhausted effector T-cells. , 2016, Current opinion in virology.

[9]  R. Ahmed,et al.  Features of responding T cells in cancer and chronic infection. , 2010, Current opinion in immunology.

[10]  S. Zhong,et al.  High-throughput illumina strand-specific RNA sequencing library preparation. , 2011, Cold Spring Harbor protocols.

[11]  G. Freeman,et al.  Enhancing SIV-Specific Immunity In Vivo by PD-1 Blockade , 2008, Nature.

[12]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  G. Freeman,et al.  Restoring function in exhausted CD8 T cells during chronic viral infection , 2006, Nature.

[14]  R. Siliciano,et al.  Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations , 2015, Nature.

[15]  E. Wherry,et al.  Overcoming T cell exhaustion in infection and cancer. , 2015, Trends in immunology.

[16]  E. Wherry,et al.  Cutting Edge: Rapid In Vivo Killing by Memory CD8 T Cells1 , 2003, The Journal of Immunology.

[17]  H. Cantor,et al.  Regulation of self-tolerance by Qa-1-restricted CD8(+) regulatory T cells. , 2011, Seminars in immunology.

[18]  E. Wherry,et al.  Molecular and cellular insights into T cell exhaustion , 2015, Nature Reviews Immunology.

[19]  G. Pantaleo,et al.  PD-1+ and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals , 2016, Nature Medicine.

[20]  D. Speiser,et al.  T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? , 2014, Nature Reviews Immunology.

[21]  R. Siliciano,et al.  HIV-specific CD8⁺ T cells and HIV eradication. , 2016, The Journal of clinical investigation.

[22]  Yin C Lin,et al.  The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells , 2011, Nature Immunology.

[23]  S. Crotty.  T follicular helper cell differentiation, function, and roles in disease. , 2014, Immunity.

[24]  J. Harty,et al.  Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1. , 2010, Immunity.

[25]  J. Cyster,et al.  Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1High Germinal Center-Associated Subpopulation1 , 2007, The Journal of Immunology.

[26]  Xia Yang,et al.  The transcription factor TCF-1 initiates the differentiation of TFH cells during acute viral infection , 2015, Nature Immunology.

[27]  J. Cyster,et al.  Follicular stromal cells and lymphocyte homing to follicles , 2000, Immunological reviews.

[28]  E John Wherry,et al.  T cell exhaustion , 2011 .

[29]  G. Freeman,et al.  Reinvigorating exhausted HIV-specific T cells via PD-1–PD-1 ligand blockade , 2006, The Journal of experimental medicine.

[30]  P. Greenberg,et al.  Tolerance and exhaustion: defining mechanisms of T cell dysfunction. , 2014, Trends in immunology.

[31]  Veronica D. Gonzalez,et al.  CXCR5+ CCR7– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles , 2007, European journal of immunology.

[32]  Y. Zhuang,et al.  E proteins in lymphocyte development and lymphoid diseases. , 2014, Current topics in developmental biology.

[33]  W. Leonard,et al.  Interleukin-21 Is a Critical Cytokine for the Generation of Virus-Specific Long-Lived Plasma Cells , 2013, Journal of Virology.

[34]  L. Picker,et al.  A B cell follicle sanctuary permits persistent productive SIV infection in elite controllers , 2014, Nature Medicine.

[35]  R. Ahmed,et al.  Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection , 2006, The Journal of experimental medicine.

[36]  M. McCausland,et al.  Quantitative PCR technique for detecting lymphocytic choriomeningitis virus in vivo. , 2008, Journal of virological methods.

[37]  G. Freeman,et al.  Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1) , 2013, Proceedings of the National Academy of Sciences.