The costimulation-regulated duration of PKB activation controls T cell longevity

  title={The costimulation-regulated duration of PKB activation controls T cell longevity},
  author={Jianxun Song and Shahram Salek-Ardakani and Paul R. Rogers and M Cheng and Luk van Parijs and Michael Croft},
  journal={Nature Immunology},
A brief antigenic stimulus can promote T cell proliferation, but the duration and nature of intracellular signals required for survival are unclear. Here we show that in the absence of OX40 costimulation, antigen-activated CD4+ cells are short-lived because the activity of protein kinase B (PKB; also known as Akt) is not maintained over time. Activated T cells that express a dominant-negative variant of PKB also undergo apoptosis, reproducing the OX40-deficient phenotype. In contrast, an active… 

Intracellular Signals of T Cell Costimulation

Intacellular costimulation signals that regulate T cell proliferation, cell cycle progression, cytokine production, survival, and memory development are discussed.

Persistence and Tumor Regression Costimulation in Promoting T Cell Cooperation between Molecular Targets of

It is found that CD8 (cid:1) effector T cells expressing both Bcl-x L and survivin strongly expanded at an early stage and had a long-term survival advantage over cells transduced with either molecule alone, and new insights into why costimulatory signals might need to be sustained over time are provided.

Cooperation between Molecular Targets of Costimulation in Promoting T Cell Persistence and Tumor Regression1

Results indicate that Bcl-xL and survivin can critically contribute in a cooperative, nonredundant manner to augment the accumulation and persistence of CD8+ T cells following encounter with Ag, and suggest a potential novel approach to augment cellular immunotherapy for cancer.

Regulation of A1 by OX40 Contributes to CD8+ T Cell Survival and Anti-Tumor Activity

OX40 signals regulate CD8 T cell survival at least in part through maintaining expression of the anti-apoptotic molecule A1, and provide new insight into the mechanism by which OX40 may impact anti-tumor immunity.

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection

Functional redundancy of A1 with other pro-survival BCL-2 family members in the control of T cell-dependent immune responses is suggested.

The role of OX40-mediated co-stimulation in T-cell activation and survival.

OX40 ligation has been shown to augment CD4 and CD8 T-cell clonal expansion, effector differentiation, survival, and in some cases, abrogate the suppressive activity of regulatory FoxP3+CD25+CD4+ T cells.

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo1

It is shown that CD4 and CD8 T cells depend on TNFR type 2 (p75) for survival during clonal expansion, allowing larger accumulation of effector cells and conferring protection from apoptosis for a robust memory pool in vivo.

Enhanced T Cell Apoptosis within Drak2-Deficient Mice Promotes Resistance to Autoimmunity1

It is shown that, in the absence of DRAK2 signaling, T cells require greater tonic signaling for maintenance during clonal expansion and the potential that D RAK2 blockade may lead to permanent autoimmune T cell destruction via intrinsic apoptosis pathways is highlighted.



CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL.

The OX40 Costimulatory Receptor Determines the Development of CD4 Memory by Regulating Primary Clonal Expansion1

It is demonstrated that OX40-OX40L interactions control primary T cell expansion and the ability to retain high numbers of Ag-specific T cells and can promote survival of greater numbers of T cells with time and control the size of the memory T cell pool.

Expression of Active Protein Kinase B in T Cells Perturbs Both T and B Cell Homeostasis and Promotes Inflammation1

It is demonstrated that aged mice develop lymphadenopathy and splenomegaly that result from an accumulation of CD4, CD8, and unexpectedly B cells, and T cell expression of active protein kinase B can alter T cell homeostasis, indirectly influence B cell homeOSTasis, and promote inflammation in vivo.

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

Enhancement of T cell metabolism by Akt and more rapid CD28‐independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity.

Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor κb Activation, and Bcl-XL Levels in Vivo

A physiological role for PKB in promoting survival of DP thymocytes and mature T cells is highlighted, and evidence for the direct association of three major survival molecules (PKB, Bcl-XL, and NF-κB) in vivo in T lymphocytes is provided.

Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?

  • M. Croft
  • Biology, Medicine
    Nature Reviews Immunology
  • 2003
Several members of the tumour-necrosis factor receptor (TNFR) superfamily — OX40, 4-1BB, CD27, CD30 and HVEM (herpes-virus entry mediator) — are poised to deliver co-stimulatory signals both early and late after encounter with antigen.

Costimulation via OX40L Expressed by B Cells Is Sufficient to Determine the Extent of Primary CD4 Cell Expansion and Th2 Cytokine Secretion In Vivo

The results suggest that without engagement of OX40L on B cells, CD4 cell responses to many protein Ag would be dominated by Th1 cytokines, which have important implications for strategies to achieve optimal priming of CD4 subsets.