Abstract:
Controversy persists regarding the molecular and functional changes in T cells as they differentiate from naive cells after exposure to antigen. We have developed a new in vitro CD4+ TCm model that has helped clarify some of the key discrepancies between different models of memory T cell differentiation. Firstly, we demonstrated that IL-7 promotes memory T cell establishment, supporting the concept that access to IL-7 at the end of a response may restrict access to the memory cell pool in a stochastic manner. A short antigenic stimulation, prior to the onset of cell division, was shown to promote TCM-like cell generation and sustained stimulation of newly developing progeny was required for further differentiation. TCM-like cells were shown to evolve from a transient CCR7l0W/‘state following removal of stimulation. We found an effector phase was not a pre-requisite to TCM-like cell formation, and TCM-like cells can self-renew through subsequent short stimulations. Enhanced functionality of TCM-like cells was associated with a faster response to stimulation, secretion of high titres of IFN-y, and a reduced threshold to antigen, although sufficient costimulation independence was not observed. Expression of the B7- and TNF-families of costimulatory ligand/receptor molecules was highly dynamic following TCR stimulation, but these changes did not differ appreciably between the naive and TCM-like populations. CD8+ TCM-like cells generated using the same in vitro model, were impaired in their proliferative capacity, although their cell surface phenotype, was similar to CD4+ TCM-like cells. This impairment was party relieved by preconditioning naive CD8+ T cells with IL-12 during antigenic stimulation, which was shown to enhance proliferation, associated with an increase in IL-2 secretion capacity. However, CD8+ TCM-like cells remained dependent on CD4+ T cell help to execute the most robust proliferative response, independent of IL-2. In summary, we have provided evidence in support of the progressive differentiation model, proposing a naive-»TCM~>TEM linear pathway for memory T cell differentiation. Generating CD8+ TCM-like cells using the same model revealed important differences between CD4+ and CD8+ T cells in their differing requirements to generate robust responses. Appreciating these differences will be crucial to tailoring immunotherapies to optimally exploit both lymphocyte subsets.