Direct Interferon-γ Signaling Dramatically Enhances CD4+ and CD8+ T Cell Memory

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

IFN-γ Receptor Signaling Regulates Memory CD8+ T Cell Differentiation

Sercan

Stoycheva

Hämmerling

et al. 2010

“…Anti-V␣2 clone B20.1 and anti-V␤8.3 clone 1B3.3 were purchased from BD Pharmingen. For intracellular staining, cells were cultured in the presence of brefeldin-A and gp [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] for CD4 T cells or gp [33][34][35][36][37][38][39][40][41] for CD8 T cells or no peptide. Intracellular cytokines were detected using eBioscience Abs specific for IFN-␥ clone XMG1.2 or IL-2 clone JES6-5H4.…”

Section: Flow Cytometrymentioning

confidence: 99%

Increasing the CD4+ T Cell Precursor Frequency Leads to Competition for IFN-γ Thereby Degrading Memory Cell Quantity and Quality

Whitmire

Benning

Eam

et al. 2008

Self Cite

The precursor frequency of naive CD4+ T cells shows an inverse relationship with the number of memory cells generated after exposure to cognate Ag. Using the lymphocytic choriomeningitis virus (LCMV) model, we show here that only when the initial number of naive virus-specific CD4+ T cell precursors is low (≤104 per spleen) do they give rise to abundant and homogeneous memory cells that are CD62Llow, IL-7Rhigh, and imbued with an enhanced capacity to produce cytokine, proliferate, and survive over time. Furthermore, memory cells derived from a high naive precursor number show functional deficits upon secondary exposure to virus. The negative effect of higher naive precursor frequency was not attributable to competition for limiting amounts of Ag, because LCMV-naive CD4+ TCR-transgenic CD4 T cells were recruited into the LCMV-induced response even when their initial number was high. Instead, the T cells appear to compete for direct IFN-γ signals as they differentiate into memory cells. These results are consistent with a model of T cell development in which the most fit effector T cells that receive sufficient direct IFN-γ signals are selected to differentiate further into memory cells.

“…Whereas IFN-g regulates T cell number in many Ag-based systems, these studies have not always addressed whether these outcomes result from its effects on T cell differentiation, on APCs, or other immune cells, and are in some instances confounded by its effect on T cell proliferation (23,(34)(35)(36)(37). Indeed, the deficiency of IFN-g also compromises AICD (38), a pathway by which activated T cells generated in response to high concentrations of Ag or in situations of chronic infection or autoreactive cells are deleted (9).…”

Section: Discussionmentioning

confidence: 99%

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

Purushothaman

Marcel

Garg

et al. 2013

Lineage-committed T effectors generated in response to Ag during the inflammatory phase are destined to die during termination of the immune response. We present evidence to suggest that molecular signatures of lineage commitment are reflected in apoptotic cascades activated in CD4+ T effectors. Exemplifying this, ablation of inducible NO synthase (iNOS) protected effector-memory T (TEM) cells, but not TNaive or central-memory T cells, activated in vitro, from apoptosis triggered by cytokine deprivation. Furthermore, attrition of T effectors generated in the secondary, but not the primary, response to Ag was substantially reduced in mice, which received iNOS inhibitors. Distinct patterns of iNOS expression were revealed in wild-type TEM effectors undergoing apoptosis, and ablation of iNOS protein in primary and TEM wild-type effectors confirmed observations made in iNOS−/− cells. Describing molecular correlates of this dependence, mitochondrial damage, activation of the protein Bax, and release from mitochondria of the apoptosis-inducing factor were selectively abrogated in iNOS−/− TEM effectors. Suggesting that iNOS dependence was linked to the functional identity of T cell subsets, both iNOS induction and apoptosis were compromised in IFN-γ−/− TEM effectors, which mirrored the response patterns of iNOS−/− TEM. Collectively, these observations suggest that programs regulating deletion and differentiation are closely integrated and likely encoded during lineage commitment of T effectors.