Table 2.

Summary of the biological and molecular functions of T-cell costimulatory molecules

MoleculeLigand(s)Receptor expression patternBiological functionMolecular functionReferences
Coinhibitory
CTLA4B7-1 (CD80), B7-2 (CD86)Activated T cells, TregNegative T-cell costimulation (primarily at priming); prevent tonic signaling and/or attenuate high-affinity clonesCompetitive inhibition of CD28 costimulation (binding of B7-1 and B7-2)(8, 10–12, 38, 157–161)
PD-1PD-L1, PD-L2Activated T cells, NK cells, NKT cells, B cells, macrophages, subsets of DC; as a result of inflammationNegative T-cell costimulation (primarily in periphery); attenuate peripheral activity, preserve T-cell function in the context of chronic antigenAttenuate proximal TCR signaling, attenuate CD28 signaling(32–35, 38, 39, 53, 100, 162–165)
PD-L1PD-1, B7-1 (CD80)Inducible in DC, monocytes, macrophages, mast cells, T cells, B cells, NK cellsAttenuate T-cell activity in inflamed peripheral tissuesPD-1 ligation; cell-intrinsic mechanism unclear(33, 34, 102)
LAG3MHC-II, LSECtinActivated CD4 and CD8 T cells, NK cells, TregNegative regulator of T-cell expansion; control T-cell homeostasis; DC activationCompetitive binding to MHC-II; proximal LSECtin mechanism unknown(133, 134, 166–170)
TIM3Galectin-9, PtdSer, HMGB1, CEACAM-1Th1 CD4 and Tc1 CD8, Treg, DC, NK cells, monocytesNegative regulation of Type 1 immunity; maintain peripheral toleranceNegative regulation of proximal TCR components; differences between ligands unclear(135–139, 171)
TIGITPVR (CD155), PVRL2 (CD112)CD4 and CD8, Treg, TFH, NK cellsNegative regulation of T-cell activity; DC tolerizationCompetitive inhibition of DNAM1 (CD226) costimulation (binding of PVR), binding of DNAM1 in cis; cell-intrinsic ITIM-negative signaling(144, 145, 172–176)
VISTACounter-receptor unknownT cells and activated Treg, myeloid cells, mature APCNegative regulation of T-cell activity; suppression of CD4 T cellsIncrease threshold for TCR signaling, induce FOXP3 synthesis; proximal signaling unknown(140, 141, 146, 147, 177, 178)
Costimulatory
ICOSICOSLActivated T cells, B cells, ILC2Positive costimulation; Type I and II immune responses; Treg maintenance; TFH differentiationp50 PI3K recruitment (AKT signaling); enhance calcium signaling (PLCγ)(179–186)
OX40OX40LActivated T cells, Treg, NK cells, NKT cells, neutrophilsSustain and enhance CD4 T-cell responses; role in CD8 T cells and TregsRegulation of BCL2/XL (survival); enhance PI3K/AKT signaling(187–193)
GITRGITRLActivated T cells, Treg, B cells, NK cells, macrophagesInhibition of Tregs; costimulation of activated T cells, NK cell activationSignal through TRAF5(194–200)
4-1BB (CD137)4-1BBLActivated T cells, Treg, NK cells, monocytes, DC, B cellsPositive T-cell costimulation; DC activationSignal through TRAF1, TRAF2(201–205)
CD40CD40LAPCs, B cells, monocytes, nonhematopoietic cells (e.g., fibroblasts, endothelial cells)APC licensingSignal through TRAF2, 3, 5, 6; TRAF-independent mechanisms?(206–209)
CD27CD70CD4 and CD8 T cells, B cells, NK cellsLymphocyte and NK cell costimulation; generation of T-cell memorySignal through TRAF2, TRAF5(210–214)
  • NOTE: A summary of the ligands, immunologic expression pattern, biological function, and molecular mechanisms is presented for selected costimulatory and coinhibitory receptors. Molecular functions (i.e., downstream signaling) reflect predominant currently known mechanisms, but additional mechanisms are likely to contribute significantly.

  • Abbreviations: NK, natural killer; NKT, natural killer T cell; TFH, T follicular helper; TRAF, tumor necrosis factor receptor–associated factors; DC, dendritic cell.