Memories are made of this...

Infection with the parasite Leishmania causes considerable morbidity and mortality, against which there is no effective human vaccine. Both humans and mice can resolve primary infections and become resistant to further infection, but some parasites persist and might contribute to long-term protection by maintaining the presence of effector T cells. If persistent antigen is required for long-term protection, then developing a non-live vaccine against leishmaniasis will be difficult. In this study, Phillip Scott and colleagues characterized the CD4⁺ T-cell response during infection and showed that protective central memory T (T_CM) cells, which are not dependent on the presence of parasites, can develop in infected mice.

Memory T cells are a heterogeneous population thought to contain two distinct subsets — effector memory T (T_EFF) cells, which migrate to tissues and produce cytokines, and T_CM cells, which circulate through the lymph nodes. Scott and colleagues investigated the development of CD4⁺ memory T cells during infection of mice with Leishmania major. CD4⁺ T cells were labelled with CFSE (5,6-carboxyfluorescein diacetate succinimidyl ester) — which allows proliferative responses to be analysed by flow cytometry — and then transferred into naive recipients. After parasitic challenge infection of the recipient mice, some of these donor T cells migrated to the draining lymph nodes (dLNs) and proliferated, indicating that immune mice contain a T_CM-cell population. During proliferation, most cells downregulated their expression of the lymph-node homing molecule CD62L, indicating that these cells had differentiated into T_EFF cells. To confirm that T_CM cells present in the donor T-cell population from immune mice could differentiate into T_EFF cells and mediate protection, CD4⁺CD62L^hi T cells — which do not produce interferon-γ (IFN-γ) when stimulated with leishmanial antigens — were purified and used in transfer experiments. Again, the donor T cells proliferated in the dLN; they also developed the capacity to produce IFN-γ and could be detected at the site of infection within two weeks. Importantly, the mice that received these T_CM cells were protected from challenge infection.

To address the role of persistent antigen in the maintenance of memory T cells, a mutant L. major strain that is unable to persist in mice was used. Mice infected with this mutant L. major had no detectable parasites by 15 weeks after infection. At 25 weeks after infection, no T_EFF cells were detectable, as shown by the lack of both an IFN-γ response to leishmanial antigens in vitro and a delayed-type hypersensitivity response in vivo. However, T_CM cells were detectable at 25 weeks; CFSE-labelled CD4⁺ T cells from these mice, when transferred to naive recipients that were subsequently challenged with L. major, could migrate to and proliferate in the dLN. Furthermore, 25 weeks after the initial infection with mutant L. major, mice were protected against infection with virulent L. major, showing that the T_CM cells conferred protection.

This study shows that both T_EFF and T_CM cells contribute to immunity to L. major infection, but T_CM cells can be maintained in the absence of parasites and confer protection. Targeting T_CM cells could therefore be the basis for the development of a successful non-live vaccine against leishmaniasis.