Chronic HCV infection and the clonality of intrahepatic T cells

A broad repertoire of highly specific effector and memory T cells is required to fight the various pathogens that one encounters during life. How is this diversity achieved given that the number of genes encoding the antigen-specific Tcell receptor (TCR) is limited? The majority of T cells have a TCR composed of two chains, a and b, each chain containing one variable (V) region and one constant (C) region. TCR diversity is created during development of T cells in the thymus, when the multiple genes that encode the two chains of the TCR heterodimer are rearranged by somatic recombination. Receptors of different specificities are generated by different combinations of V, D and J gene segments, and by removal and addition of nucleotides at the VJ (TCRa) or VDJ (TCRb) junctions. Both mechanisms maximize diversity in the so called complementarity determining region 3 (CDR3), that varies in size and amino acid sequence and provides the TCR’s unique specificity [1,2]. It is this region that binds immunogenic peptides from invading pathogens and triggers the adaptive cellular immune response. Thus, analysis of the size and sequence of the CDR3 region provides a molecular footprint of the overall TCR repertoire [1]. Not surprisingly, healthy individuals typically display a Gaussian distribution of their CDR3 length repertoire at birth. With increasing age, the diversity of the CDR3 length repertoire decreases and oligoclonal T-cell expansions are frequently found in the memory T-cell population of healthy, older persons [3,4]. These oligoclonal expansions have been attributed to the increasing number of antigens that the immune system responds to during life. Especially common pathogens such as influenza A virus, cytomegalovirus, and Epstein–Barr virus [5–7], that cause latent or repeated infections, may therefore maintain and expand subpopulations of T cells with a specific TCR receptor. In addition, significant expansions of clonal and oligoclonal Tcell subpopulations have been associated with malignancies [8,9] and with autoimmune and chronic inflammatory conditions [10]. An overview of the factors that may contribute to oligoclonal expansions and need to be considered and, if possible, controlled for in studies on CDR3 length diversity, is given in Table 1. In this issue of the Journal, Vigan et al. evaluate the TCRb chain diversity in patients with hepatitis C virus (HCV) infection [11]. HCV is known for its propensity to establish persistent infection and chronic inflammatory liver injury in most infected subjects [12]. An early and multispecific T-cell response has been associated with viral clearance [13] and immune protection [14,15]. In contrast, a less efficient immune response that continues for decades in its futile attempt to eradicate the virus, has been associated with chronic inflammatory liver injury, fibrogenesis and development of liver cirrhosis [16,17]. Whether this unsuccessful immune response is targeted against fewer antigens or consists of smaller effector cell populations than a successful one, is one of the questions currently being investigated. In general, HCV-specific T cells can readily be isolated from liver biopsies and cultured and tested after in vitro expansion. Based on this technique, many studies clearly demonstrate that the intrahepatic T-cell response is multispecific even in persistently infected individuals [18–21]. However, because these studies require in vitro expansion, it is not possible to assess the size of clonal T-cell subpopulations in situ, in the infected liver. Also, it is not possible to study T-cell subpopulations that do not adapt well and do not grow in vitro. Thus, the size and diversity of HCVspecific T-cell subpopulations in the liver and their relevance for the outcome of HCV infection are still unknown. Vigan et al. address this issue with a molecular technique by determining the size and the sequence of the TCRb chain CDR3 region using RNA from paired peripheral blood mononuclear cells (PBMC) and from liver biopsies from patients with chronic HCV infection [11]. This technique, originally established by Pannetier et al. [22] is probably the most powerful and accurate technique to analyze TCR Journal of Hepatology 38 (2003) 677–680