Attack of the CD4 clones

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 

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 TCRαβ⁺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.