CD8alpha/alpha+ T-cells and Immune Memory

University dissertation from Stockholm : Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology

Abstract: A better understanding of T-cell memory formation is crucial for rationale vaccine design and the identification of correlates of immune protection. The CD8alphaalpha homodimer expressed on CD8+ T-cells is not anymore considered to represent a TCR co-receptor, it may rather represent a mechanism to modulate T-cell avidity and identify a subset of memory T-cells. The aim of the work presented in this thesis was to characterize the CD8alphaalpha+ T-cell compartment in the context of vaccination, where Tcell memory plays a pivotal role. We analyzed in Paper I the phenotype of CD8alphaalpha+ Tcells in healthy donors and in rhesus macaque monkeys (Macaca mulatta) which represent a very valuable animal model for preclinical vaccine trials. CD8alphaalpha+ T-cells were present in healthy donors and in a higher frequency in rhesus monkeys. In both species, the CD8alphaalpha+ T-cell compartment was enriched in differentiated (effector and memory) T-cells, as compared to the CD4+ and CD8alphabeta+ T-cell compartments, and displayed a polyfunctional capacity. We developed assays allowing to study the T-cell compartment in rhesus monkeys, and showed that CD8alphaalpha+ T-cells can be studied in rhesus monkeys. In Paper II, we assessed longitudinally the presence of CD8alphaalpha+ Tcells in patients with melanoma who underwent peptide-based vaccination and showed a partial or complete tumor regression. CD8alphaalpha+ T-cells represented a stable population with an effector or terminally differentiated phenotype, and Melan-A/MART-1-specific CD8alphaalpha+ T-cells were detected in one patient up to five years after vaccination. The oligoclonal TCR repertoire of CD8alphaalpha+ T-cells and the similar TCR repertoire of Melan-A/MART-1 of CD8alphaalpha+ and CD8alphabeta+ T-cells, supported our hypothesis that CD8alphaalpha+ T-cells arise from CD8alphabeta+ T-cells which downregulated CD8beta chain expression upon Ag stimulation. We identified, in Paper III, an increase of Mtb-specific CD8alphaalpha+ T-cells in rhesus monkeys after TB vaccination. The characterization of CD8alphaalpha+ T-cells phenotype in rhesus monkeys after TB vaccination and after Mtb infection was further analyzed in Paper IV. CD8alphaalpha+ T-cells underwent similar phenotypical changes as observed in the CD4+ and CD8alphabet + T-cell compartments, in vaccinated but not in non-vaccinated animals: loss of IL-7Ralpha after the first Ad boost, and transient decrease of precursor T-cells (defined by CD45RA/CCR7 expression) after Mtb challenge. These results suggest that CD8alphaalpha+ T-cells contribute to the formation of immunological memory and participate in the formation of the cellular immune response. We hypothesize that the expression of CD8alphaalpha enables to modulate the avidity of CD8+ T-cells with high affinity TCRs. Yet, the mechanisms of CD8alphaalpha+ T-cells formation need to be further elucidated. Altogether, our data underscores the role of CD8alphaalpha+ T-cells in the establishment of immune memory in humans and rhesus monkeys. The detection and characterization of Ag-specific CD8alphaalpha+ T-cells may represent a relevant marker in the context of vaccine trials and to custom-tailor immune therapeutic strategies with the aim to establish long-lived and Ag-specific immune responses.

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