Containment of hepatitis C virus (HCV) and other chronic human viral infections is associated with persistence of virus-specific CD4 T cells, but ex vivo characterization of circulating CD4 T cells has not been achieved. To further define the phenotype and function of these cells, we developed a novel approach for the generation of tetrameric forms of MHC class II/peptide complexes that is based on the cellular peptide-exchange mechanism. HLA-DR molecules were expressed as precursors with a covalently linked CLIP peptide, which could be efficiently exchanged with viral peptides following linker cleavage. In subjects who spontaneously resolved HCV viremia, but not in those with chronic progressive infection, HCV tetramer–labeled cells could be isolated by magnetic bead capture despite very low frequencies (1:1,200 to 1:111,000) among circulating CD4 T cells. These T cells expressed a set of surface receptors (CCR7+CD45RA–CD27+) indicative of a surveillance function for secondary lymphoid structures and had undergone significant in vivo selection since they utilized a restricted Vβ repertoire. These studies demonstrate a relationship between clinical outcome and the presence of circulating CD4 T cells directed against this virus. Moreover, they show that rare populations of memory CD4 T cells can be studied ex vivo in human diseases.
Cheryl L. Day, Nilufer P. Seth, Michaela Lucas, Heiner Appel, Laurent Gauthier, Georg M. Lauer, Gregory K. Robbins, Zbigniew M. Szczepiorkowski, Deborah R. Casson, Raymond T. Chung, Shannon Bell, Gillian Harcourt, Bruce D. Walker, Paul Klenerman, Kai W. Wucherpfennig
Title and authors | Publication | Year |
---|---|---|
Autoreactive T cell responses show pro-inflammatory polarization in diabetes but a regulatory phenotype in health
Sefina Arif, Timothy I Tree, Thomas P Astill, Jennifer M Tremble, Colin M Dayan, Bart O Roep, Mark Peakman |
Journal of Clinical Investigation | 2004 |
Use of HLA-B27 tetramers to identify low-frequency antigen-specific T cells in Chlamydia-triggered reactive arthritis
H Appel, W Kuon, M Kuhne, P Wu, S Kuhlmann, S Kollnberger, A Thiel, P Bowness, J Sieper |
Arthritis Research & Therapy | 2004 |
CD8 epitope escape and reversion in acute HCV infection
J Timm, GM Lauer, DG Kavanagh, I Sheridan, AY Kim, M Lucas, T Pillay, K Ouchi, LL Reyor, JS Wiesch, RT Gandhi, RT Chung, N Bhardwaj, P Klenerman, BD Walker, TM Allen |
Journal of Experimental Medicine | 2004 |
Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells
M Lucas, CL Day, JR Wyer, SL Cunliffe, A Loughry, AJ McMichael, P Klenerman |
Journal of virology | 2004 |
The physiological role of cytotoxic CD4(+) T-cells: the holy grail?
V Appay |
Clinical & Experimental Immunology | 2004 |
Phenotypic heterogeneity of antigen-specific CD4 T cells under different conditions of antigen persistence and antigen load
A Harari, F Vallelian, G Pantaleo |
European Journal of Immunology | 2004 |
Measuring T cell immunity to influenza vaccination in children after haemopoietic stem cell transplantation
WN Haining, JW Evans, NP Seth, GD Callaway, KW Wucherpfennig, LM Nadler, EC Guinan |
British Journal of Haematology | 2004 |