Molecular mechanisms of T cell co-stimulation and co-inhibition

Abstract

Co-stimulatory and co-inhibitory receptors have a pivotal role in T cell biology, as they determine the functional outcome of T cell receptor (TCR) signalling. The classic definition of T cell co-stimulation continues to evolve through the identification of new co-stimulatory and co-inhibitory receptors, the biochemical characterization of their downstream signalling events and the delineation of their immunological functions. Notably, it has been recently appreciated that co-stimulatory and co-inhibitory receptors display great diversity in expression, structure and function, and that their functions are largely context dependent. Here, we focus on some of these emerging concepts and review the mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors.

Figure 1. Co-signalling interactions in T cells

a|Co-stimulatory molecules deliver positive signals to T cells following their engagement by ligands and counter-receptors on antigen-presenting cells (APCs). Several co-stimulatory molecule interactions are bidirectional. b|Co-inhibitory molecules deliver negative signals into T cells. Cytotoxic T lymphocyte antigen 4 (CTLA4) is involved in bi-directional interactions: it inhibits T cell function after binding B7-1 and B7-2, and CTLA4-bound B7-1 and B7-2 may induce the expression of indoleamine 2,3-dioxygenase (IDO), which acts in trans to suppress activation of conventional T (T_Con) cells and promote the function of regulatory T (T_Reg) cells. c | In T_Con–T_Reg cell interactions, unidirectional co-signalling primarily inhibits T_Con cell reactivity, whereas bi-directional co-signalling may simultaneously deliver inhibitory signals to T_Con cells and positive signals to T_Reg cells. Herpes virus entry mediator (HVEM) functions as a co-stimulatory receptor on T_Con cells, but on T_Reg cells it can interact with B and T lymphocyte attenuator (BTLA) or CD160 to deliver inhibitory signals. Lymphocyte activation gene 3 protein (LAG3) and CTLA4 expressed on T_Reg cells inhibit T_Con cells, while also enhancing the suppressive function of T_Reg cells. Programmed cell death 1 (PD1) on T_Con cells is inhibitory, whereas PD1 on T_Reg cells provides signals that may enhance T_Reg cell proliferation, survival and maintenance. The role of B7-1 and B7-H1 on T_Reg cells and their role in T_Con–T_Reg interactions is unclear. d|Co-signalling interactions through multiple interfaces. B7-H1, CD28 and CTLA4 all interact with B7-1. Similarly, CD28, CTLA4 and inducible T cell co-stimulator (ICOS) seem to compete for interactions with B7-2. B7-1 and B7-2 both bind the proline-rich motif MYPPPY on CD28 and CTLA4. In humans, B7-H2 can also interact with CD28 and CTLA4 through a second unique site, allowing both CD28 and CTLA4 to potentially interact with B7-1 or B7-2 and B7-H2 simultaneously. CD28, CTLA4 and ICOS all bind a similar site on B7-H2. B7-H1 and B7-DC both interact with a similar binding site on PD1. In addition, B7-H1 can also interact with B7-1. The site of B7-H1 that interacts with B7-1 (site A) is distinct from that interacting with PD1 (site B), although overlapping residues may be used for both interactions. 4-1BBL, 4-1BB ligand; CD40L, CD40 ligand; DR3, death receptor 3; GITR, glucocorticoid-induced TNFR-related protein; GITRL, GITR ligand; LAIR1, leukocyte-associated immunoglobulin-like receptor 1; OX40L, OX40 ligand; PD1H, PD1 homologue; SLAM, signalling lymphocytic activation molecule; TCR, T cell receptor; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domains; TIM, type I transmembrane (or T cell) immunoglobulin and mucin; TL1A, TNF-like ligand A.

Figure 2. Co-stimulatory and co-inhibitory signalling pathways downstream of CD28 family receptors

Primary nodes of signalling activity downstream of T cell receptor (TCR)–CD3 and CD28 and inducible T cell co-stimulator (ICOS) co-stimulatory receptors overlap significantly. CD28 associates with proximal signalling molecules through the YMNM and PYAP motifs to co-stimulate several major signalling nodes, leading to activation of distal pathways involved in cell growth, activation of effector function and survival. ICOS lacks a PYAP motif but contains a YMFM motif that recruits the more active phosphatidylinositol 3-kinase (PI3K) subunit p50α (indicated by a thick arrow), thus leading to enhanced AKT signalling. ICOS also induces interleukin-4 (IL-4) through a C-MAF pathway. Co-inhibitory signalling downstream of B and T lymphocyte attenuator (BTLA), programmed cell death 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4) suppresses T cell activation and function through the recruitment of the phosphatases SH2 domain-containing tyrosine phosphatase 1 (SHP1), SHP2 and serine/threonine protein phosphatase 2A (PP2A). These phosphatases dephosphorylate several of the major signalling nodes that are essential for co-stimulation of T cells. PD1 has also been shown to inhibit the RAS–extracellular signal-regulated kinase (ERK) pathway. Additional co-inhibitory pathways have been posited for CTLA4, PD1 and BTLA. BTLA and CTLA4 may also transduce positive signals in some contexts. BTLA may associate with growth factor receptor-bound protein 2 (GRB2) to activate PI3K and promote T cell survival, whereas CTLA4 may also activate PI3K through a YVKM motif. AP, activator protein; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; PKCθ, protein kinase Cθ; PLCγ, phospholipase Cγ.

Figure 3. Co-signalling pathways downstream of tumour necrosis factor receptor superfamily receptors

Tumour necrosis factor (TNF) receptor superfamily (TNFRSF) receptors associate with proximal TNF receptor-associated factor (TRAF) adaptor molecules to activate primary signalling nodes that in turn activate the distal pathways that synergize with T cell receptor (TCR)–CD3 signalling pathways, resulting in enhanced cell growth, effector function and survival. Unique functions associated with TNFRSF receptors have yet to be clearly correlated with specific TRAFs in many cases. However, TRAF2 is the prototypical TRAF and is involved in c-Jun N-terminal kinase (JNK) activation, nuclear factor-κB (NF-κB) activation and anti-apoptotic signalling. TRAF5 also mediates NF-κB activation, and TRAF1 and TRAF3 also function in T cell co-stimulation and anti-apoptotic signalling. Death receptor 3 (DR3) associates with the adaptor molecule TNFR-associated death domain (TRADD), which recruits a TRAF2–receptor-interacting protein (RIP) complex that activates both NF-κB and mitogen-activated protein kinase (MAPK) signalling pathways. CD27 and glucocorticoid-induced TNFR-related protein (GITR) share the ability to associate with SIVA1, a molecule involved in apoptotic pathways, although the functional role of SIVA1 association is unclear, as CD27 and GITR function primarily as co-stimulatory molecules. The TNF receptors 4-1BB and OX40 have been shown to promote memory T cell function in the absence of TCR signalling, although the requirement of specific TRAFs and signalling pathways remains unclear. As such, it is possible that unknown adaptor molecules and/or signalling pathways remain to be identified. AP1, activator protein 1; ERK, extracellular signal-regulated kinase; HVEM, herpes virus entry mediator; IKK, inhibitor of NF-κB kinase; MEK, MAPK/ERK kinase; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cells; NIK, NF-κB-inducing kinase; PI3K, phosphatidylinositol 3-kinase; PKCθ, protein kinase Cθ; PLCγ, phospholipase Cγ; TAB, TAK1-binding protein; TAK, TGFβ-activated kinase.