Regulation of T cell responses by innate lymphoid cells (ILCs) is increasingly documented and studied. Direct or indirect crosstalk between ILCs and T cells early during and after T cell activation can affect their differentiation, polarization, and survival. Natural killer (NK) cells that belong to the ILC1 group were initially described for their function in recognizing and eliminating “altered self” and as source of early inflammatory cytokines, most notably type II interferon. Using signals conveyed by various germ-line encoded activating and inhibitory receptors, NK cells are geared to sense sudden cellular changes that can be caused by infection events, malignant transformation, or cellular stress responses. T cells, when activated by TCR engagement (signal 1), costimulation (signal 2), and cytokines (signal 3), commit to a number of cellular alterations, including entry into rapid cell cycling, metabolic changes, and acquisition of effector functions. These abrupt changes may alert NK cells, and T cells might thereby expose themselves as NK cell targets. Here, we review how activated T cells can be recognized and regulated by NK cells and what consequences such regulation bears for T cell immunity in the context of vaccination, infection, or autoimmunity. Conversely, we will discuss mechanisms by which activated T cells protect themselves against NK cell attack and outline the significance of this safeguard mechanism.

Asymmetric partitioning of fate determinants is a mechanism that contributes to T cell differentiation. However, it remains unclear whether the ability of T cells to divide asymmetrically is influenced by their differentiation state, as well as whether enforcing asymmetric cell division (ACD) rates would have an impact on T cell differentiation and memory formation. Using the murine LCMV infection model, we established a correlation between cell stemness and the ability of CD8+ T cells to undergo ACD. Transient mTOR inhibition was proven to increase ACD rates in naïve and memory cells and to install this ability in exhausted CD8+ T cells. Functionally, enforced ACD correlated with increased memory potential, leading to more efficient recall response and viral control upon acute or chronic LCMV infection. Moreover, transient mTOR inhibition also increased ACD rates in human CD8+ T cells. Transcriptional profiling revealed that progenies emerging from enforced ACD exhibited more pronounced early memory signatures, which functionally endowed these cells with better survival in the absence of antigen exposure and more robust homing to secondary lymphoid organs, providing critical access to survival niches. Our data provide important insights into how ACD can improve long-term survival and function of T cells and open new perspectives for vaccination and adoptive T cell transfer therapies.

Cytomegalovirus (CMV) infection induces an atypical CD8 T cell response, termed inflationary, that is characterised by accumulation and maintenance of high numbers of effector memory like cells in circulation and peripheral tissues—a feature being successfully harnessed for vaccine purposes. Although stability of this population depends on recurrent antigen encounter, the requirements for prolonged survival in peripheral tissues remain unknown. Here, we reveal that murine CMV-specific inflationary CD8 T cells are maintained in an antigen-independent manner and have a half-life of 12 weeks in the lung tissue. This half-life is drastically longer than the one of phenotypically comparable inflationary effector cells. IL-15 alone, and none of other common γ-cytokines, was crucial for survival of inflationary cells in peripheral organs. IL-15, mainly produced by non-hematopoietic cells in lung tissue and being trans-presented, promoted inflationary T cell survival by increasing expression of Bcl-2. These results indicate that inflationary CD8 T cells are not just simply effector-like cells, rather they share properties of both effector and memory CD8 T cells and they appear to be long-lived cells compared to the effector cells from acute virus infections.

Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance.

2Protective CD8 + T cell-mediated immunity requires a massive expansion in cell number and the development of long-lived memory cells. Using forward genetics in mice, we identified an orphan protein named Lymphocyte Expansion Molecule (LEM) that promoted antigen-dependent CD8 + T cell proliferation, effector function and memory cell generation in response to infection with lymphocytic choriomeningitis virus. Generation of LEM-deficient mice confirmed these results.Through interaction with CR6 interacting factor (CRIF1), LEM controlled the levels of oxidative phosphorylation (OXPHOS) complexes and respiration resulting in the production of pro-proliferative mitochondrial Reactive Oxygen Species (mROS).LEM provides a link between immune activation and the expansion of protective CD8 + T cells driven by OXPHOS and represents a pathway for the restoration of long-term protective immunity based on metabolically modified CTL. 3Cytotoxic CD8 + T cells (CTL) are a central arm of the immune system responsible for protection from intracellular viruses and cancer because they kill infected or transformed cells (1). Since chronic virus infection (2) and cancer (3) are wide spread diseases it is clear that CTL-immunity often fails. A major reason for this failure is because high viral (4, 5) or tumor (6-8) load results in either deletion or functional inactivation (known as immune exhaustion) of CTL. The result is failure in both short-term CTL immunity and immunological memory because memory CD8 T cell development is blocked (9). Impaired expansion is an important cause of deletion and immune exhaustion and results in the failure to produce sufficient numbers of protective CTL and memory cells (5). Retro mutant mice have increased immunity to chronic viral infectionInfection of wild-type C57BL/6 mice with the clone 13 variant of lymphocytic choriomeningitis virus (LCMV C13) is an established model for human chronic viral infection resulting in a massive viral load that causes both deletion and immune exhaustion of CTL and a block in memory CD8 T cell development (10).We examined the CTL response to LCMV C13 infection after germ-line mutagenesis to identify mutants with enhanced immunity. To this end, 430 third-generation (G3) ethyl-N-nitrosourea (ENU)-induced germ-line mutants were produced in a C57BL/6J background (11). G3 mice were infected with LCMV C13 and after 8 days the level of LCMV-specific CD8 T cells measured in the spleen by staining with a tetramer for the np396 LCMV peptide and flow-cytometry (12). Three independent germ-line transmissible modifications, which resulted in increased levels of LCMV-specific 4 CD8 T cells were isolated, of which one (a semi-dominant) was bred to homozygosity (Fig. S1a). We named this strain Retro.Homozygous Retro mutant mice showed a 10-fold increase in CD8 T cells specific for LCMV np396 peptide compared to wild-type (WT) and a smaller but significant increase in the number of CTL specific for the gp33-LCMV peptide ( Fig. 1 a, b).Compared to WT mice, a smaller percentage of Retr...