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Degeneracy of Antigen Recognition as the Molecular Basis for the High Frequency of Naive A2/Melan-A Peptide Multimer⁺ CD8⁺ T Cells in Humans

Valérie Dutoit¹, Verena Rubio-Godoy¹, Mikäel J. Pittet¹, Alfred Zippelius¹, Pierre-Yves Dietrich², Frédérique Anne Legal², Philippe Guillaume³, Pedro Romero¹, Jean-Charles Cerottini³, Richard A. Houghten⁴, Clemencia Pinilla⁴ and Danila Valmori¹

¹ Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital (CHUV), 1011 Lausanne, Switzerland
² Division of Oncology, Laboratory of Tumor Immunology, University Hospital (HUG), Geneva 1211, Switzerland
³ Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges 1066, Switzerland
⁴ Torrey Pines Institute for Molecular Studies and Mixture Science Inc., San Diego, CA 92121

Address correspondence to Danila Valmori, Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, Avenue Pierre-Decker 4, 1011 Lausanne, Switzerland. Phone: 4121-31401-78; Fax: 4121-31474-77; E-mail: danila.valmori{at}inst.hospvd.ch

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.

Key Words: Melan-A-naive-CD8-A2 • naive • CD8 • A21 peptide multimers • repertoire

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