Characterization of immune modulating functions of γδ T cell subsets in a gnotobiotic pig model of human rotavirus infection

BackgroundAnti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8+ antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1+ mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.ResultsIL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8+ T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8+ T cells but not γδ T cells.ConclusionsMechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.

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Characterization of HIV-induced remodeling reveals differences in infection susceptibility of memory CD4+ T cell subsets in vivo

Cell Reports ◽

10.1016/j.celrep.2021.109038 ◽

2021 ◽

Vol 35 (4) ◽

pp. 109038

Author(s):

Guorui Xie ◽

Xiaoyu Luo ◽

Tongcui Ma ◽

Julie Frouard ◽

Jason Neidleman ◽

...

Keyword(s):

T Cell ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Infection Susceptibility

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Identification of leptospiral protein antigens recognized by WC1+ γδ T cell subsets as target for development of recombinant vaccines

10.1101/2021.07.16.452762 ◽

2021 ◽

Author(s):

Aline Teixeira ◽

Alexandria Gillespie ◽

Alehegne Yirsaw ◽

Emily Britton ◽

Janice Telfer ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Outer Membrane Proteins ◽

Γδ T Cells ◽

T Cell Response ◽

T Cell Subsets ◽

Economic Losses ◽

Γδ T Cell ◽

Protein Antigens

Pathogenic Leptospira species cause leptospirosis, a neglected zoonotic disease recognized as a global public health problem. It is also the cause of the most common cattle infection that results in major economic losses due to reproductive problems. γδ T cells play a role in the protective immune response in livestock species against Leptospira while human γδ T cells also respond to Leptospira. Thus, activation of γδ T cells has emerged as a potential component for optimization of vaccine strategies. Bovine γδ T cells proliferate and produce IFN-γ in response to vaccination with inactivated leptospires and this response is mediated by a specific subpopulation of the WC1-bearing γδ T cells. WC1 molecules are members of the group B scavenger receptor cysteine rich (SRCR) superfamily and are composed of multiple SRCR domains, of which particular extracellular domains act as ligands for Leptospira. Since WC1 molecules function as both pattern recognition receptors and γδ TCR coreceptors, the WC1 system has been proposed as a novel target to engage γδ T cells. Here, we demonstrate the involvement of leptospiral protein antigens in the activation of WC1+ γδ T cells and identified two leptospiral outer membrane proteins able to interact directly with them. Interestingly, we show that the protein-specific γδ T cell response is composed of WC1.1+ and WC1.2+ subsets, although a greater number of WC1.1+ γδ T cells respond. Identification of protein antigens will enhance our understanding of the role γδ T cells play in the leptospiral immune response and in recombinant vaccine development.

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