Memory CD4 T cells emerge from effector T-cell progenitors

Abstract

A hallmark of adaptive immunity is the generation of memory T cells that confer long-lived, antigen-specific protection against repeat challenges by pathogens. Understanding the mechanisms by which memory T cells arise is important for rational vaccination strategies and improved therapeutic interventions for chronic infections and autoimmune disorders. The large clonal expansion of CD8 T cells in response to some infections has made the development of CD8 T-cell memory more amenable to study, giving rise to a model of memory cell differentiation in which a fraction of fully competent effector T cells transition into long-lived memory T cells. Delineation of CD4 T-cell memory development has proved more difficult as a result of limitations on tracking the smaller populations of CD4 effector T cells generated during a pathogenic challenge, complicating efforts to determine whether CD4 memory T cells are direct descendants of effector T cells or whether they develop by alternative pathways. Here, using two complementary cytokine reporter mouse models to identify interferon (IFN)-gamma-positive effector T cells and track their fate, we show that the lineage relationship between effector and memory CD4 T cells resembles that for CD8 T cells responding to the same pathogen. We find that, in parallel with effector CD8 T cells, IFN-gamma-positive effector CD4 T cells give rise to long-lived memory T cells capable of anamnestic responses to antigenic rechallenge.

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

“…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…”

Apoptotic Programs Are Determined during Lineage Commitment of CD4+ T Effectors: Selective Regulation of T Effector-Memory Apoptosis by Inducible Nitric Oxide Synthase

“…Whereas TEM and TCM may arise from IFN-g-producing precursors (23), the production of IFN-g is a signature output of Ag-induced activation of TEM (3,24). Therefore, to test whether dependence on iNOS is linked to differentiation of TEM, apoptosis of TEM effectors was assessed using mice with a targeted deletion of IFN-g (25).…”