IL-12 selectively programs effector pathways that are stably expressed in human CD8+ effector memory T cells in vivo

Abstract

IntroductionThe pool of circulating CD8 ϩ cytotoxic T lymphocytes (CTLs) is remarkably heterogeneous, consisting of antigen inexperienced naive cells as well as multiple populations of effector and memory subsets. 1 Various models have been proposed to explain the genesis of memory subsets, and a significant body of evidence suggests that long-lived memory cells are derived from early effector cells that survive contraction as antigen loads wane. 2 If so, then the diverse spectrum of memory cells that fall into either effector memory (T EM ) or central memory (T CM ) categories would also be predicted to be derived from a common pool of primary effectors. 3 Regardless of their origins, T EM and T CM differ substantially in their functional capabilities, and the extrinsic signals that regulate their development are complex and multifactorial. Among these factors, innate cytokines are key signals that regulate effector cell differentiation, 4 with IL-12 and type I interferon (IFN-␣/␤) playing important roles in both effector and memory cell development. 5 In humans, CD8 ϩ subsets have been distinguished based on their differential expression of various markers, including CD45RA, CD27, CD28, CCR7, CD62L, CD127, and CXCR3. [6][7][8][9] Based solely on the expression of CCR7 and CD45RA, early studies defined 4 main subsets: naive (CD45RA ϩ /CCR7 ϩ ), T CM (CD45RA Ϫ / CCR7 ϩ ), T EM (CD45RA Ϫ /CCR7 Ϫ ), and effector memory-RA (T EMRA , CD45RA ϩ /CCR7 Ϫ ). 10 Aside from their differential expression of CD45RA and other cell surface markers, T EM uniformly exhibit rapid effector functions in response to antigen activation. Further, T EM do not generally require CD28-mediated costimulation or innate cytokines to secrete proinflammatory cytokines or to lyse target cells. 11,12 Thus, if T EM cells are direct descendants of effector CTLs, then the maintenance of effector functions within T EM would suggest early programming during the priming phase of infection.In mice, both IL-12 and IFN-␣/␤ exert somewhat overlapping and redundant effects by driving effector cell development. 5,[13][14][15][16][17] Although IL-12 seems to be more potent at promoting IFN-␥ secretion, both IL-12 and IFN-␣/␤ are equally effective at regulating lytic activity in murine CD8 ϩ T cells. In contrast, IL-12 and IFN-␣/␤ appear to play very distinct roles in priming human CD8 ϩ T-cell responses. Recently, Ramos et al demonstrated a preferential role for IL-12 over IFN-␣/␤ in driving cytokine expression and lytic activity in human CTLs. 18 Conversely, IFN-␣/␤ enhanced the development of a subpopulation of cells that displayed phenotypic and functional characteristics of T CM . Programming of effectors by IL-12 was accompanied by progression of cells through cell division and was altered by the strength of TCR engagement. IL-12 programmed effector cell development, which was regulated by induction of the IL-12 receptor at each division as cells proliferated in response to TCR activation. In contrast, IFN-␣/␤ tended to slow the progression of cell divi...

Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells

“…To gauge whether the loss of CD8+ Treg suppressive ability during disease exacerbation could be restored, we used the cytokine IL-12, which has been shown to significantly enhance the CD8+ T cell’s effector ability [28–30]. First, bulk PBMCs from healthy subjects were cultured with either no cytokine, IL-12 (25 μg/mL) or IL-23 (25 μg/mL) for seven days after which CD8+ T cells were isolated and used in suppression assays with autologous CD4+CD25− T cell responders isolated from freshly thawed PBMCs.…”

IFN-α Suppresses GATA3 Transcription from a Distal Exon and Promotes H3K27 Trimethylation of the CNS-1 Enhancer in Human Th2 Cells

“…We further assessed GATA3 mRNA expression in dividing populations of cells undergoing differentiation in response to IL-4 or IFN-α (19, 24). Cells were labeled with CFSE, activated with anti-CD3/CD28 for 5 days, and then purified by sorting based on CFSE dilution as indicated by the gates in Fig.…”

New insights into IL-12-mediated tumor suppression

“…29 Additionally, IL-12 programs effector T cells for optimal generation of effector memory T cells and T follicular helper cells. 30,31 Direct effects of IL-12 on APCs have also been reported. Even though the activation of IL-12R in these cells did not involve the canonical STAT pathway, it increased their ability to present poorly immunogenic tumor peptides.…”