IL3-Driven T Cell-Basophil Crosstalk Enhances Antitumor Immunity.

Cytotoxic T lymphocytes (CTL) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in CTL exhaustion. This study investigates the role of interleukin-3 (IL3) in orchestrating antitumor immunity through CTL modulation. We found that intratumoral CTLs exhibited a progressive decline in IL3 production, which was correlated with impaired cytotoxic function. Augmenting IL3 supplementation, through intraperitoneal administration of recombinant IL3, IL3-expressing tumor cells, or IL3-engineered CD8+ T cells, conferred protection against tumor progression, concomitant with increased CTL activity. CTLs were critical for this therapeutic efficacy as IL3 demonstrated no impact on tumor growth in Rag1 knockout mice or following CD8+ T-cell depletion. Rather than acting directly, CTL-derived IL3 exerted its influence on basophils, concomitantly amplifying antitumor immunity within CTLs. Introducing IL3-activated basophils retarded tumor progression, whereas basophil depletion diminished the effectiveness of IL3 supplementation. Furthermore, IL3 prompted basophils to produce IL4, which subsequently elevated CTL IFNγ production and viability. Further, the importance of basophil-derived IL4 was evident from the absence of benefits of IL3 supplementation in IL4 knockout tumor-bearing mice. Overall, this research has unveiled a role for IL3-mediated CTL-basophil cross-talk in regulating antitumor immunity and suggests harnessing IL3 sustenance as a promising approach for optimizing and enhancing cancer immunotherapy. See related Spotlight, p. 798.

Providing a Helping Hand: Metabolic Regulation of T Follicular Helper Cells and Their Association With Disease.

T follicular helper (Tfh) cells provide support to B cells upon arrival in the germinal center, and thus are critical for the generation of a robust adaptive immune response. Tfh express specific transcription factors and cellular receptors including Bcl6, CXCR5, PD-1, and ICOS, which are critical for homing and overall function. Generally, the induction of an immune response is tightly regulated. However, deviation during this process can result in harmful autoimmunity or the inability to successfully clear pathogens. Recently, it has been shown that Tfh differentiation, activation, and proliferation may be linked with the cellular metabolic state. In this review we will highlight recent discoveries in Tfh differentiation and explore how these cells contribute to functional immunity in disease, including autoimmune-related disorders, cancer, and of particular emphasis, during infection.