CD8alpha/alpha+ T-cells and immune memory

Abstract

A better understanding of T-cell memory formation is crucial for rationale vaccine design and the identification of correlates of immune protection. The CD8αα 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 CD8αα+ T-cell compartment in the context of vaccination, where T-cell memory plays a pivotal role. We analyzed in Paper I the phenotype of CD8αα+ T-cells in healthy donors and in rhesus macaque monkeys (Macaca mulatta) which represent a very valuable animal model for preclinical vaccine trials. CD8αα+ T-cells were present in healthy donors and in a higher frequency in rhesus monkeys. In both species, the CD8αα+ T-cell compartment was enriched in differentiated (effector and memory) T-cells, as compared to the CD4+ and CD8αβ+ T-cell compartments, and displayed a polyfunctional capacity. We developed assays allowing to study the T-cell compartment in rhesus monkeys, and showed that CD8αα+ T-cells can be studied in rhesus monkeys.

In Paper II, we assessed longitudinally the presence of CD8αα+ T- cells in patients with melanoma who underwent peptide-based vaccination and showed a partial or complete tumor regression. CD8αα+ T-cells represented a stable population with an effector or terminally differentiated phenotype, and Melan-A/MART-1-specific CD8αα+ T-cells were detected in one patient up to five years after vaccination. The oligoclonal TCR repertoire of CD8αα+ T-cells and the similar TCR repertoire of Melan-A/MART-1 of CD8αα+ and CD8αβ+ T-cells, supported our hypothesis that CD8αα+ T-cells arise from CD8αβ+ T-cells which downregulated CD8β chain expression upon Ag stimulation.

We identified, in Paper III, an increase of Mtb-specific CD8αα+ T-cells in rhesus monkeys after TB vaccination. The characterization of CD8αα+ T-cells phenotype in rhesus monkeys after TB vaccination and after Mtb infection was further analyzed in Paper IV. CD8αα+ T-cells underwent similar phenotypical changes as observed in the CD4+ and CD8αβ+ T-cell compartments, in vaccinated but not in non-vaccinated animals: loss of IL-7Rα after the first Ad boost, and transient decrease of precursor T-cells (defined by CD45RA/CCR7 expression) after Mtb challenge. These results suggest that CD8αα+ 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 CD8αα enables to modulate the avidity of CD8+ T-cells with high affinity TCRs. Yet, the mechanisms of CD8αα+ T-cells formation need to be further elucidated.

Altogether, our data underscores the role of CD8αα+ T-cells in the establishment of immune memory in humans and rhesus monkeys. The detection and characterization of Ag-specific CD8αα+ 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.