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Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer3,4. Here we show that an interleukin-4 fusion protein (Fc–IL-4), a typical type 2 cytokine, directly acts on CD8+ T cells and enriches functional terminally exhausted CD8+ T (CD8+ TTE) cells in the tumour. Consequently, Fc–IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc–IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8+ TTE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc–IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE cells. These findings underscore Fc–IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.Fc–IL-4, a typical type 2 cytokine, reinvigorates exhausted CD8+ T cells in tumours, underscoring this fusion protein as a potent immunotherapy that synergizes effectively with type 1 immunity against cancer. [ABSTRACT FROM AUTHOR]

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity. Editor's summary: After initial antigen encounter, some T cells persist and differentiate into long-lived memory cells. This process is accompanied by metabolic reprogramming that supports survival and memory functions, but the key factors driving memory T cell metabolic adaptation remain unclear. Using mouse models of viral infection and melanoma, Bevilacqua et al. found that the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) supports the switch from aerobic glycolysis to oxidative metabolism during central memory CD8+ T cell formation. PPARβ/δ expression was required for memory T cell responses upon rechallenge, as well as the generation of TCF-1+ progenitor exhausted T cells during chronic antigen exposure. Together, these findings identify PPARβ/δ as a key regulator of metabolic reprogramming during memory T cell differentiation. —Claire Olingy [ABSTRACT FROM AUTHOR]

The Ly49 natural killer (NK) cell receptors are class I MHC-specific inhibitory receptors that are distributed to overlapping NK cell subsets. The formation of the Ly49 receptor repertoire was examined with transgenic mice that express Ly49A in all NK cells. In MHC class I-deficient mice, the Ly49A transgene did not prevent expression of endogenous Ly49 genes. However, in H-2(d) mice that express a Ly49A ligand, the transgene caused clear alterations in the endogenous Ly49 repertoire. The frequency of NK cells expressing another H-2(d)-specific receptor, Ly49G2(+), was substantially reduced. Reduced numbers of cells expressing endogenous Ly49A was suggested by reduced endogenous Ly49A mRNA levels. These results support the existence of an MHC-dependent education process that limits the number of NK cells that coexpress multiple self-specific Ly49 receptors. Ligand-dependent downregulation of Ly49 cell surface levels was also examined. Cell-surface downregulation occurred even when the transgene was expressed at low levels. The results demonstrate that downregulation of Ly49A cell surface levels is a posttranscriptional event, and argue against a model in which Ly49 receptors are calibrated to specific cell surface levels depending on the available class I ligands.

In response to infection, naïve CD8+ T (TN) cells yield a large pool of short-lived terminal effector (TTE) cells that eliminate infected host cells. In parallel, a minor population of stem cell–like central memory (TCM) cells forms, which has the capacity to maintain immunity after pathogen clearance. It has remained uncertain whether stem-like TCM cells arise by dedifferentiation from a subset of cytolytic TTE cells or whether priming generates stem-like cells capable of seeding the TCM compartment and, if so, when cytolytic TTE cells branch off. Here, we show that CD8+ T cells with stem-like properties, which are identified by the expression of TCF1 (encoded by Tcf7), are present across the primary response to infection. Priming programs TN cells to undergo multiple cell divisions, over the course of which TCF1 expression is maintained. These TCF1+ cells further expand relatively independently of systemic inflammation, antigen dose, or affinity, and they quantitatively yield TCF1+ TCM cells after pathogen clearance. Inflammatory signals suppress TCF1 expression in early divided TCF1+ cells. TCF1 down-regulation is associated with the irreversible loss of self-renewal capacity and the silencing of stem/memory genes, which precedes the stable acquisition of a TTE state. TCF1 expression restrains cell cycling, explaining in part the limited expansion of TCF1+ relative to TCF1− cells during the primary response. Thus, our data are consistent with terminal differentiation of effector cells being a step-wise process that is initiated by inflammation in primed stem-like cells, which would otherwise become central memory cells by default. Editor's summary: The adaptive immune system is characterized by the ability to generate long-lived memory cells that provide protection against reinfection. Yet it is uncertain how a pool of stem-cell like central memory T cells (TCM) develops after pathogen encounter. Silva et al. used mouse models to track the emergence and fate of central memory precursor T cells (TpCM) during the first exposure to lymphocytic choriomeningitis virus (LCMV). These TpCM were detected early after infection, were present throughout the acute phase of the immune response, and were predisposed to become TCM, although they could form effector T cells when exposed to inflammatory signals. Additionally, the ability to generate TpCM in response to certain vaccination models indicates conditions that might instruct the formation of immune memory optimally. —Sarah H. Ross [ABSTRACT FROM AUTHOR]

Ly49A is an inhibitory receptor, which counteracts natural killer (NK) cell activation on the engagement with H-2[D.sup.d] ([D.sup.d]) MHC class I molecules (MHC-I) on target cells. In addition to binding [D.sup.d] on apposed membranes, Ly49A interacts with [D.sup.d] ligand expressed in the plane of the NK cells' membrane, indeed, multivalent, soluble MHC-I ligand binds inefficiently to Ly49A unless the NK cells' [D.sup.d] complexes are destroyed. However, it is not known whether masked Ly49A remains constitutively associated with cis [D.sup.d] also during target cell interaction. Alternatively, it is possible that Ly49A has to be unmasked to significantly interact with its ligand on target cells. These two scenarios suggest distinct roles of Ly49A/[D.sup.d] cis interaction for NK cell function. Here, we show that Ly49A contributes to target cell adhesion and efficiently accumulates at synapses with [D.sup.d]-expressing target cells when NK cells themselves lack [D.sup.d]. When NK cells express [D.sup.d], Ly49A no longer contributes to adhesion, and ligand-driven recruitment to the cellular contact site is strongly reduced. The destruction of [D.sup.d] complexes on NK cells, which unmasks Ly49A, is necessary and sufficient to restore Ly49A adhesive function and recruitment to the synapse. Thus, cis [D.sup.d] continuously sequesters a considerable fraction of Ly49A receptors, preventing efficient Ly49A recruitment to the synapse with [D.sup.d]+ target cells. The reduced number of Ly49A receptors that can functionally interact with [D.sup.d] on target cells explains the modest inhibitory capacity of Ly49A in [D.sup.d] NK cells. This property renders Ly49A NK cells more sensitive to react to diseased host cells. cis interaction | immune synapse | inhibitory receptor