The mTOR kinase determines effector versus memory cell fate of CD8+ T cells by regulating T-bet and Eomesodermin expression

By Rajesh R. Rao, Qingsheng Li, K. Odunsi, P. Shrikant. Immunity, 2010

660 citations recorded by the source corpus.

SUMMARY The mechanisms underpinning integration of instructions that program naïve CD8+ T cells for effector and/or memory differentiation are not well understood. Herein, we demonstrate that IL-12, the critical determinant that instructs antigen-stimulated naïve CD8+ (OT-I) T cells for T-bet dependent heritable type I effector maturation, enhances and sustains Ag/B7.1 induced mTOR activity via PI3K and STAT4 pathways. Blocking mTOR activity by rapamycin reverses IL-12 induced heritable type I effector functions due to loss of persistent T-bet expression. Remarkably, rapamycin treatment of IL-12 conditioned OT-I cells promotes persistent Eomesodermin expression and produces memory-precursors that demonstrate enhanced sustenance and antigen-recall responses upon adoptive transfer. Surprisingly, the memory-precursors show greater tumor efficacy than IL-12 conditioned effector OT-I cells. These results identify mTOR as the “central” regulator of transcriptional programs that determine effector and/or memory cell-fates in CD8+ T cells. Targeting mTOR activity offers new opportunities to regulate CD8+ T cell mediated immunity.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/3e410953c86f0843d869648b640b981f6ba1085f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Rafi Ahmed
2. M. Bevan
3. F. Sallusto
4. A. Lanzavecchia
5. Nu Zhang
6. K. Araki
7. Erika L. Pearce
8. T. Malek

In Oncology

1. F. Sallusto
2. A. Lanzavecchia
3. Rafi Ahmed
4. Russell G. Jones
5. Nu Zhang
6. Erika L. Pearce
7. I. Castro
8. T. Malek

Citations in the corpus

• Regulation of Immune Responses by mTOR (2011, background): “Treatment with rapamycin and metformin can enhance memory formation in antitumor responses (26, 106, 108).”
• From Vaccines to Memory and Back (2010, positive): “Recent studies have identified an additional approach by means of drugs that directly act on T cells to regulate memory differentiation (Araki et al., 2009; Pearce et al., 2009; Rao et al., 2010).”
• The mammalian Target of Rapamycin (mTOR) regulates T helper cell differentiation through the selective activation of mTORC1 and mTORC2 signaling (2011, background): “Moreover, mTOR controls the development of CD8 + memory T cells in part by regulating expression of the transcription factors T-bet and eomesodermi”
• Metabolic Regulation of Immune Responses (2014, background): “Although the metabolic importance of mTORC1 in CD8+ memory T cells remains to be explored, its inhibition by rapamycin has been shown to increase their numbers and enhance their function in both mice and nonhuman primates (105, 106).”
• Interleukin-2 Receptor Signaling: At the Interface between Tolerance and Immunity (2010, positive): “Rapamycinsensitive mTOR, downstream of the PI3K-AKT pathway, represents a candidate because it modulates the expression of both T-bet and Eomes (Delgoffe et al., 2009; Rao et al., 2010).”
• Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. (2016, background): “In fact, many basic and clinical studies have associated rapamycin with active immune responses (49, 50).”
• CD8+ T Cells: Foot Soldiers of the Immune System (2011, positive): “Mechanistically, IL-12 promotes effector CD8 + T cell differentiation through the induction of T-bet (Joshi et al., 2007; Takemoto et al., 2006) via an mTOR-dependent pathway (Rao et al., 2010).”
• Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “Consistent with this, the drug rapamycin, which also inhibits mTORC1, enhances the generation of CD8 TM cells (17, 19, 20).”