Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors

Abstract

Many vaccination strategies and immune cell therapies aim at increasing the numbers of memory T cells reactive to protective antigens. However, the differentiation lineage and therefore the optimal generation conditions of CD4 memory cells remain controversial. Linear and divergent differentiation models have been proposed, suggesting CD4 memory T cell development from naive precursors either with or without an effector-stage intermediate, respectively. Here, we address this question by using newly available techniques for the identification and isolation of effector T cells secreting effector cytokines. In adoptive cell transfers into normal, nonlymphopenic mice, we show that long-lived virus-specific memory T cells can efficiently be generated from purified interferon γ–secreting T helper (Th) type 1 and interleukin (IL)-4– or IL-10–secreting Th2 effectors primed in vitro or in vivo. Importantly, such effector-derived memory T cells were functional in viral challenge infections. They proliferated vigorously, rapidly modulated IL-7 receptor expression, exhibited partial stability and flexibility of their cytokine patterns, and exerted differential effects on virus-induced immunopathology. Thus, cytokine-secreting effectors can evade activation-induced cell death and develop into long-lived functional memory cells. These findings demonstrate the efficiency of linear memory T cell differentiation and encourage the design of vaccines and immune cell therapies based on differentiated effector T cells.

Persistence of effector memory Th1 cells is regulated by Hopx

“…Th1 cells have been described to be more susceptible to Fas-mediated apoptosis than Th2 [14][15][16][17] and Th17 cells [18][19][20]. However, Th1 cells can be long lived and drive chronic inflammation [6][7][8][9][10][11][12][13], and can persist as effector/memory cells efficiently [24][25][26]65]. Obviously, compensatory regulatory mechanisms have to exist in those cells.…”

“…In vitro, Th1 cells are much more sensitive to Fas-mediated apoptosis than Th2 or Th17 cells [14][15][16][17][18][19][20]. In vivo, however, effector/memory Th1 cells are abundant in chronically inflamed tissue [21][22][23] and persist over long time periods [24][25][26], suggesting that their sensitivity to Fas-mediated apoptosis is strictly regulated. Here, we demonstrate that among CD4 1 T cells, the transcriptional cofactor homeobox only protein (Hopx) is expressed by repeatedly restimulated Th1 cells, but not by Th2, Th17 or regulatory T cells.…”

Immunological memories of the bone marrow

“…This is surprising as already in 1964, McGregor and Gowans demonstrated that secondary immune responses are not impaired when all circulating lymphocytes are removed by chronic thoracic duct drainage 91. Yet, considering that circulation is their lifestyle, usually cells from spleen are adoptively transferred into blood, to analyze their persistence again in the spleen of the host 61, 63…”

“…The “half‐life” of blood‐borne antigen‐experienced T cells in the phase of slow contraction shows a tremendous variation, ranging from 8 to 15 years, upon smallpox vaccination of humans60 to less than 40‐60 days, in mice immunized with a peptide of lymphocytic choriomeningitis virus or ovalbumin 59. In mice, the numbers of adoptively transferred and experienced CD4 + and CD8 + T cells decline with half‐lives of 15‐70 days, in the absence of antigen 61, 62. Such adoptively transferred CD8 + or CD4 + T cells can provide protection 61, 63, 64, 65, 66…”

“…On the other hand, antigen‐experienced T cells of murine spleen can survive and proliferate, when adoptively transferred into hosts which do not bear the antigen,61, 63 arguing that in the absence of antigen, circulating memory T cells are maintained and induced to proliferate by cytokines, ie, by homeostatic proliferation. Homeostatic proliferation of memory T cells from murine spleen has been analyzed by Becker and colleagues, who transferred splenic CD8 + T cells into naive hosts 94, 95, 110, 111, 112, 113.…”