Degeneracy of antigen recognition as the molecular basis for the high frequency of naive A2/Melan-a peptide multimer(+) CD8(+) T cells in humans.
In contrast with the low frequency of most single epitope reactive T cells in the preimmune repertoire, up to 1 of 1,000 naive CD8(+) T cells from A2(+) individuals specifically bind fluorescent A2/peptide multimers incorporating the A27L analogue of the immunodominant 26-35 peptide from the melanocyte differentiation and melanoma associated antigen Melan-A. This represents the only naive antigen-specific T cell repertoire accessible to direct analysis in humans up to date. To get insight into the molecular basis for the selection and maintenance of such an abundant repertoire, we analyzed the functional diversity of T cells composing this repertoire ex vivo at the clonal level. Surprisingly, we found a significant proportion of multimer(+) clonotypes that failed to recognize both Melan-A analogue and parental peptides in a functional assay but efficiently recognized peptides from proteins of self- or pathogen origin selected for their potential functional cross-reactivity with Melan-A. Consistent with these data, multimers incorporating some of the most frequently recognized peptides specifically stained a proportion of naive CD8(+) T cells similar to that observed with Melan-A multimers. Altogether these results indicate that the high frequency of Melan-A multimer(+) T cells can be explained by the existence of largely cross-reactive subsets of naive CD8(+) T cells displaying multiple specificities.
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital (CHUV), 1011 Lausanne, Switzerland.
Valérie
V
Dutoit
Verena
V
Rubio-Godoy
Mikäel J
MJ
Pittet
Alfred
A
Zippelius
Pierre-Yves
PY
Dietrich
Frédérique Anne
FA
Legal
Philippe
P
Guillaume
Pedro
P
Romero
Jean-Charles
JC
Cerottini
Richard A
RA
Houghten
Clemencia
C
Pinilla
Danila
D
Valmori
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D003429:Cross Reactions; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058965:MART-1 Antigen; D046911:Macromolecular Substances; D008545:Melanoma / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
D000951:Antigens, Neoplasm; D001324:Autoantigens; D016056:Immunodominant Epitopes; D058965:MART-1 Antigen; C548667:MLANA protein, human; D046911:Macromolecular Substances; D009363:Neoplasm Proteins