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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1750-1751. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by ten Berge, I. J. M. Articles by van Lier, R. A. W. Search for Related Content PubMed Articles by ten Berge, I. J. M. Articles by van Lier, R. A. W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Crompton et al, page 2053 Attack of the CD4 clones Ineke J. M. ten Berge, and René A. W. van Lier ACADEMIC MEDICAL CENTRE, AMSTERDAM Latent human cytomegalovirus (CMV) infection is associated with vast clonal expansions of cytotoxic CD8+ and CD4+ T cells. The human persistent herpes virus CMV has evolved in close relationship with its host, during which it has developed a wide variety of strategies to escape the immune system, which in its turn has responded with a refined series of defense lines. Latent CMV infection is accompanied by an increase in the number of circulating resting, effector-type CD4+ and CD8+ T cells with constitutive cytolytic activity. Although it is yet unsettled whether these cells are all CMV specific, it has become clear that T-cell responses to CMV are among the broadest and strongest analyzed so far, occupying a considerable fraction of the T-cell compartment.1 Cytotoxic CD28–CD4+ T cells emerge during primary CMV infection just following the decrease in viral load (see figure). Importantly, a considerable fraction of these cells can lyse CMV-antigen–expressing target cells, restricted by HLA class II. The CMV-specific cytotoxic CD28–CD4+ T cells present during latency were shown to have developed, through very strong selection, from the virus-specific cells early in primary infection.2 View larger version (28K): [in this window] [in a new window]   Longitudinal course of CD28–CD4+ T cells in relation to CMV viral load after transplantation of a kidney from a CMV-seropositive donor into a CMV-seronegative recipient. Squares indicate viral load; circles, percentage of CD28–CD4+ T cells in peripheral blood.   In this issue of Blood, Crompton and colleagues describe the cytotoxic CD4+ T-cell response specific to the DYS peptide (DYSNTHSTRYV) from the CMV glycoprotein B (gB), restricted through HLA-DRB*0701. They show that this response constitutes a very large proportion of the total CMV-specific CD4+ T-cell response in HLA-DRB*0701 individuals. Remarkably, their study reveals a clear immunodominance for this CD4+ immune response, as reflected by a striking conservation of T-cell receptor (TCR) sequence between different individuals. In that respect, it resembles the CMV-specific CD8+ immune response, which is characterized by a high degree of clonal selection in vivo.3 Crompton et al also show that TCR usage by these CMV-gB–specific CD4+ T cells is highly homologous to that in HLA-DRB*0701 patients with monoclonal TCRβ+CD4+ T–large granular lymphocyte (T-LGL) lymphocytosis,4 strongly suggesting that the CMV-gB peptide may be one of the driving forces behind this clonal expansion. Still, in light of the high prevalence of CMV infection in humans (about 75%) and the rather frequent prevalence of HLA-DRB1*0701 (about 30%) in the white population, the rare occurrence of these monoclonal expansions implies that additional factors are involved in the pathogenesis of CD4+ T-LGL. The immune response toward CMV is aimed at maintaining latency in infected individuals, but recent studies, like the present one, indicate that this response nevertheless occurs at the expense of the heterogeneity of the T-cell repertoire. Moreover, a huge amount of potential harmful effector cells is generated, which may produce proinflammatory cytokines and execute cytotoxicity that can cause substantial collateral damage in excess of what is needed to suppress the virus. Thus, design of a vaccine or immunotherapy against CMV should include the correlates of a protective immune response against the virus with avoidance of induction of the strong effector T-cell increase as seen in natural CMV infection. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. REFERENCES Sylwester AW, Mitchell BL, Edgar JB, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 2005; 202:673–685.[Abstract/Free Full Text] van Leeuwen EM, Remmerswaal EB, Heemskerk MH, ten Berge I, van Lier RA. Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. Blood 2006; 108:3121–3127.[Abstract/Free Full Text] Day EK, Carmichael AJ, ten Berge I, et al. Rapid CD8+ T cell repertoire focusing and selection of high-affinity clones into memory following primary infection with a persistent human virus: human cytomegalovirus. J. Immunol 2007; 179:3203–3213.[Abstract/Free Full Text] Garrido P, Ruiz-Cabello F, Barcena P, et al. Monoclonal TCR-Vbeta13.1+/CD4+/NKa+/CD8-/+dim T-LGL lymphocytosis: evidence for an antigen-driven chronic T-cell stimulation origin. Blood 2007; 109:4890–4898.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals Laura Crompton, Naeem Khan, Rajiv Khanna, Laxman Nayak, and Paul A. H. Moss Blood 2008 111: 2053-2061. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by ten Berge, I. J. M. Articles by van Lier, R. A. W. Search for Related Content PubMed Articles by ten Berge, I. J. M. Articles by van Lier, R. A. W. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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