Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as damage-associated molecular patterns or alarmins, remains ill defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8(+) T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a CTL-intrinsic fashion, determined plurifunctional effector cell differentiation, and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses.

How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8(+) T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8(+) T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8(+) T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8(+) T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8(+) T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness.

B. performed experiments on HBV-infected patients, analysed data, prepared the figures and edited the manuscript; C.B. and F.G. analysed the expression of genes involved in IL-2 sensing on KCs; A.C. and L.N. generated the lentiviral vectors encoding IL-2; G.G.-A. generated recombinant adeno-associated viruses; W.V.B. and D.D.P. generated rLCMV vectors; M.K., R.O. and L.G.G. provided funding, conceptual advice and edited the manuscript; M.I. designed and coordinated the study, provided funding, analysed the data, and wrote the paper.

During infection, the release of damage-associated molecular patterns, so-called "alarmins," orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4 + T cells of the Th2 and regulatory subsets.Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virusspecific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell-intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus-specific CD4 + T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches.IL-33 | ST2 | CD4 T cell | Th1 cell | virus infection I ntercellular signaling molecules, such as cytokines and damageassociated molecular patterns (DAMPs), are essential for the induction and amplification of immune responses. DAMPs are multifunctional host proteins that indicate tissue damage. They are also referred to as alarmins, because they serve as early warning signals to activate innate and adaptive immune responses (1). The alarmin IL-33, a member of the IL-1 family, is constitutively expressed in the nucleus of endothelial and epithelial cells and is released during tissue damage and necrosis (2). Upon release, IL-33 mediates its activity through a heterodimeric cell surface receptor consisting of the ubiquitous IL-1R accessory protein (IL1RAcP) and the more selectively expressed receptor ST2, also known as T1 and IL-1RL1 (3, 4). The intracellular signaling pathway of this receptor complex includes the recruitment of MyD88 and leads to the activation of NF-κB, ERK, p38, and JNK pathways (2).IL-33 acts on a wide range of immune cells, but has been implicated predominantly in Th2-associated immune responses (5). Nonetheless, this categorization has recently been challenged by reports describing IL-33 as an enhancer of IFN-γ production by iNKT cells, NK cells, and CD8+ T cells (6-8). In addition, IL-33 signaling is important for the activation and functionality of cytotoxic CD8 + T cells during viral infection (9). In the present work, we studied a potential impact of IL-33 on Th1 cell responses in vitro and in vivo. In the course of infection with LCMV, which potently induces Th1-differentiated effector CD4 + T cells (10), we found that many of the virus-specific CD4 + T cells expressed the IL-33 receptor ST2. ST2 ex...