Protein synthesis, degradation, and energy metabolism in T cell immunity

T cell activation, proliferation, and differentiation into effector and memory states involve massive remodeling of T cell size and molecular content and create a massive increase in demand for energy and amino acids. Protein synthesis is an energy- and resource-demanding process; as such, changes in T cell energy production are intrinsically linked to proteome remodeling. In this review, we discuss how protein synthesis and degradation change over the course of a T cell immune response and the crosstalk between these processes and T cell energy metabolism. We highlight how the use of high-resolution mass spectrometry to analyze T cell proteomes can improve our understanding of how these processes are regulated

Phosphoinositide 3-Kinase p110 Delta Differentially Restrains and Directs Naïve Versus Effector CD8⁺ T Cell Transcriptional Programs

Phosphoinositide 3-kinase p110 delta (PI3K p110δ) is pivotal for CD8+ T cell immune responses. The current study explores PI3K p110δ induction and repression of antigen receptor and cytokine regulated programs to inform how PI3K p110δ directs CD8+ T cell fate. The studies force a revision of the concept that PI3K p110δ controls metabolic pathways in T cells and reveal major differences in PI3K p110δ regulated transcriptional programs between naïve and effector cytotoxic T cells (CTL). These differences include differential control of the expression of cytolytic effector molecules and costimulatory receptors. Key insights from the work include that PI3K p110δ signalling pathways repress expression of the critical inhibitory receptors CTLA4 and SLAMF6 in CTL. Moreover, in both naïve and effector T cells the dominant role for PI3K p110δ is to restrain the production of the chemokines that orchestrate communication between adaptive and innate immune cells. The study provides a comprehensive resource for understanding how PI3K p110δ uses multiple processes mediated by Protein Kinase B/AKT, FOXO1 dependent and independent mechanisms and mitogen-activated protein kinases (MAPK) to direct CD8+ T cell fate

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8⁺ T Cell Tolerance Checkpoint to High-Dose Antigen

Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice. In contrast, NDFIP1 was dispensable for peripheral deletion to low-dose exogenous or pancreatic islet-derived antigen and had little impact upon effector responses to Listeria or acute LCMV infection. These data provide evidence that NDFIP1 mediates a CD8+ T cell tolerance checkpoint, with a different mechanism to CD4+ T cells, and indicates that CD8+ T cell deletion and anergy are molecularly separable checkpoints.This work was funded by NIH grant U19-AI100627, by an Australian Government Research Training Program Domestic Scholarship (to M.V.W.), by a Sydney Parker Smith Postdoctoral Research Fellowship from the Cancer Council of Victoria (to J.M.M.), and by the National Health and Medical Research Council (NHMRC) through Program Grants 1016953, 1113904, and 1054925, Australia Fellowship 585490 (to C.C.G.), Senior Principal Research Fellowship 1081858 (to C.C.G.), CJ Martin Early Career Fellowship 585518 (to I.A.P.), and Independent Research Institutes Infrastructure Support Scheme Grant 361646. Florey Institute of Neuroscience and Mental Health and WEHI acknowledge the strong support from the Victorian Government and in particular funding from the Operational Infrastructure Support Grant

IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes

Intraepithelial lymphocytes (IEL) respond to IL-15 complexed with IL-15Ra but how this intrinsically affects IEL is unclear. Here the authors use proteomics analyses of the main mouse IEL subsets and identify PIM kinases as essential for IEL proliferation, metabolism and effector function downstream of IL-15

Cyton2:A Model of Immune Cell Population Dynamics That Includes Familial Instructional Inheritance

Lymphocytes are the central actors in adaptive immune responses. When challenged with antigen, a small number of B and T cells have a cognate receptor capable of recognising and responding to the insult. These cells proliferate, building an exponentially growing, differentiating clone army to fight off the threat, before ceasing to divide and dying over a period of weeks, leaving in their wake memory cells that are primed to rapidly respond to any repeated infection. Due to the non-linearity of lymphocyte population dynamics, mathematical models are needed to interrogate data from experimental studies. Due to lack of evidence to the contrary and appealing to arguments based on Occam’s Razor, in these models newly born progeny are typically assumed to behave independently of their predecessors. Recent experimental studies, however, challenge that assumption, making clear that there is substantial inheritance of timed fate changes from each cell by its offspring, calling for a revision to the existing mathematical modelling paradigms used for information extraction. By assessing long-term live-cell imaging of stimulated murine B and T cells in vitro, we distilled the key phenomena of these within-family inheritances and used them to develop a new mathematical model, Cyton2, that encapsulates them. We establish the model’s consistency with these newly observed fine-grained features. Two natural concerns for any model that includes familial correlations would be that it is overparameterised or computationally inefficient in data fitting, but neither is the case for Cyton2. We demonstrate Cyton2’s utility by challenging it with high-throughput flow cytometry data, which confirms the robustness of its parameter estimation as well as its ability to extract biological meaning from complex mixed stimulation experiments. Cyton2, therefore, offers an alternate mathematical model, one that is, more aligned to experimental observation, for drawing inferences on lymphocyte population dynamics

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice. In contrast, NDFIP1 was dispensable for peripheral deletion to low-dose exogenous or pancreatic islet-derived antigen and had little impact upon effector responses to Listeria or acute LCMV infection. These data provide evidence that NDFIP1 mediates a CD8+ T cell tolerance checkpoint, with a different mechanism to CD4+ T cells, and indicates that CD8+ T cell deletion and anergy are molecularly separable checkpoints.This work was funded by NIH grant U19-AI100627, by an Australian Government Research Training Program Domestic Scholarship (to M.V.W.), by a Sydney Parker Smith Postdoctoral Research Fellowship from the Cancer Council of Victoria (to J.M.M.), and by the National Health and Medical Research Council (NHMRC) through Program Grants 1016953, 1113904, and 1054925, Australia Fellowship 585490 (to C.C.G.), Senior Principal Research Fellowship 1081858 (to C.C.G.), CJ Martin Early Career Fellowship 585518 (to I.A.P.), and Indepen- dent Research Institutes Infrastructure Support Scheme Grant 361646. Florey Institute of Neuroscience and Mental Health and WEHI acknowledge the strong support from the Victorian Government and in particular funding from the Operational Infrastructure Support Grant