Clonotypic structure of the human CD4+ memory T cell response to cytomegalovirus.
High steady-state frequencies of CMV-specific CD4(+) memory T cells are maintained in CMV-exposed subjects, and these cells are thought to play a key role in the immunologic control of this permanent infection. However, the essential components of this response are poorly defined. Here, we report the use of a step-wise application of flow cytometric and molecular techniques to determine the number and size of the TCR Vbeta-defined clonotypes within freshly obtained CMV-specific CD4(+) memory T cell populations of four healthy, CMV-exposed human subjects. This analysis revealed a stable clonotypic hierarchy in which 1-3 dominant clonotypes are maintained in concert with more numerous subdominant and minor clonotypes. These dominant clonotypes accounted for 10-50% of the overall CMV response, and comprised from 0.3 to 4.0% of peripheral blood CD4(+) T cells. Two subjects displayed immunodominant responses to single epitopes within the CMV matrix phosphoprotein pp65; these single epitope responses were mediated by a single dominant clonotype in one subject, and by multiple subdominant and minor clonotypes in the other. Thus, the CMV-specific CD4(+) T cell memory repertoire in normal subjects is characterized by striking clonotypic dominance and the potential for epitope focusing, suggesting that primary responsibility for immunosurveillance against CMV reactivation rests with a handful of clones recognizing a limited array of CMV determinants. These data have important implications for the understanding of mechanisms by which a genetically stable chronic viral pathogen such as CMV is controlled, and offer possible insight into the failure of such control for a genetically flexible pathogen like HIV-1.
Bitmansour
A D
AD
Vaccine and Gene Therapy Institute, Oregon Health Sciences University, Portland, OR 97201, USA.
Waldrop
S L
SL
Pitcher
C J
CJ
Khatamzas
E
E
Kern
F
F
Maino
V C
VC
Picker
L J
LJ
D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D023201:CD40 Ligand / Q000096:biosynthesis; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D003587:Cytomegalovirus / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D016056:Immunodominant Epitopes / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D037181:Lectins, C-Type; D008297:Male; D005810:Multigene Family / Q000276:immunology; D010750:Phosphoproteins / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D014763:Viral Matrix Proteins / Q000276:immunology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D023201:CD40 Ligand; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D037181:Lectins, C-Type; D010750:Phosphoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014763:Viral Matrix Proteins; D000099192:CD69 Antigens; C065418:cytomegalovirus matrix protein 65kDa