Stem-Like Characteristics in a Subset of CD161 Expressing Human Memory CD4+ T Cells Facilitates Their Survival After Chemotherapy

CD4⁺ helper T cells are indispensible in shaping the adaptive immune system and play an important role in protection against infections. The establishment of a wide range of long-lived pathogen-specific T cells, which are ready-to-act upon second encounter with the specific pathogen, is a fundamental property of the adaptive immune response. However, the mechanisms by which antigen specific helper T are sustained long-term and resist insult by lymphocytotoxic agents is not well defined. A recent report described the existence of a long-lived CD8⁺ memory T cell population with stem cell-like properties (Turtle et al, Immunity 2009) including the ability to efflux cellular toxins through the ATP-binding cassette (ABC)–superfamily multidrug efflux protein ABCB1. We hypothesized that a subset of memory T cells with stem-like properties also exists within the CD4⁺ T cell compartment.

Here we identified a subset of memory CD4⁺ T cells with rapid drug-effluxing ability. We showed that drug effluxing CD4⁺T cells have a remarkable phenotypic similarity to CD8⁺ stem-like memory T cells described by Turtle et al and are defined as CD161⁺CD95⁺CD45RA^-CD127^hiCD28⁺CD25^int. Furthermore, effluxing CD4⁺CD161⁺ T cells proliferated poorly in response to anti-CD3/CD28 stimulation compared to their CD161^- counterpart, indicating that this subset of quiescent T cells may resist insult by cytotoxic agents through a number of different mechanisms.

We demonstrated that CD4⁺CD161⁺ T cells are enriched within the viral-specific T cell repertoire and persist after chemotherapy for AML. The high ABCB1-mediated drug efflux capacity of CD4⁺ CD161⁺ memory cells facilitated their resistance to daunorubicin in vitro and, this resistance was abrogated by the addition of competitive inhibitors of ABCB1 and ABCC1. Finally we demonstrated that following vaccination with seasonal influenza vaccine (Flu), CD161 expression was significantly higher on Flu-specific CD4+ T cells at 2 years, compared to 4 weeks post-vaccination, (74.3% ± 4.6% vs. 49.3% ± 3.5% p=< 0.007), suggesting that CD161 is a marker for long-lived Ag specific memory T cells. These data have significant implications for the development of novel adoptive therapy strategies using long-lived stem-like memory T cells.