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Immune responses must be tightly regulated to ensure both optimal protective immunity and tolerance. Costimulatory pathways within the B7:CD28 family provide essential signals for optimal T cell activation and clonal expansion. They provide crucial inhibitory signals that maintain immune homeostasis, control resolution of inflammation, regulate host defense, and promote tolerance to prevent autoimmunity. Tumors and chronic pathogens can exploit these pathways to evade eradication by the immune system. Advances in understanding B7:CD28 pathways have ushered in a new era of immunotherapy with effective drugs to treat cancer, autoimmune diseases, infectious diseases, and transplant rejection. Here, we discuss current understanding of the mechanisms underlying the coinhibitory functions of CTLA-4, PD-1, PD-L1:B7-1 and PD-L2:RGMb interactions and less studied B7 family members, including HHLA2, VISTA, BTNL2, and BTN3A1, as well as their overlapping and unique roles in regulating immune responses, and the therapeutic potential of these insights. Tight regulation of immune responses is critical. In this review, Sharpe and colleagues review inhibitory members of the B7-CD28 family and their roles in regulating immune responses with an emphasis on CTLA-4, PD-1, and the increasingly complex network of cis and trans interactions with their ligands in lymphoid organs and the periphery with implications for infection, autoimmunity, and anti-tumor immunity. [ABSTRACT FROM AUTHOR]

CD4+ T cells share common developmental pathways with CD8+ T cells, and upon maturation, CD4+ T conventional T (Tconv) cells lack phenotypic markers that distinguish these cells from FoxP3+ T regulatory cells. We developed a tamoxifen-inducible ThPOK CreERT2.hCD2 line with Frt sites inserted on either side of the CreERT2-hCD2 cassette, and a Foxp3 Ametrine-FlpO strain, expressing Ametrine and FlpO in Foxp3+ cells. Breeding these mice resulted in a CD4conviCreERT2-hCD2 line that allows for the specific manipulation of a gene in CD4+ Tconv cells. As FlpO removes the CreERT2-hCD2 cassette, CD4+ Treg cells are spared from Cre activity, which we refer to as allele conditioning. Comparison with an E8IiCreERT2.GFP mouse that enables inducible targeting of CD8+ T cells, and deletion of two inhibitory receptors, PD-1 and LAG-3, in a melanoma model, support the fidelity of these lines. These engineered mouse strains present a resource for the temporal manipulation of genes in CD4+ T cells and CD4+ Tconv cells. [Display omitted] • ThPOK CreERT2.hCD2 mice restrict Cre activity to CD4+ T cells • Foxp3 Ametrine-FlpO and ThPOK F/F.iCreERT2.hCD2 mice generate a CD4conviCreERT2-hCD2 line • CD4+ Tconv cell-type restriction of Cre activity obtained using allele conditioning • CD4conviCreERT2-hCD2 selectively removed PD-1 and LAG-3 on CD4+ Tconv cells only CD4+ T cell subpopulations have been difficult to genetically interrogate because of shared pathways with CD8+ T cells during T cell development. Using an allele-conditioning strategy, Andrews et al. generate murine lines that temporally restrict Cre activity and gene deletion to CD4+ T conventional cells, while sparing CD4+ T regulatory cells. [ABSTRACT FROM AUTHOR]