IMGT Colliers de Perles and IgSF domain standardization for T cell costimulatory activatory (CD28, ICOS) and inhibitory (CTLA4, PDCD1 and BTLA) receptors

Abstract

T cell activation depends on the specific recognition by their T cell receptors (TR) of antigenic peptides bound to major histocompatibility complex (pMHC). Optimal T cell responses occur when T cells not only receive antigen-specific signals through the TR but also non-antigen-specific costimulatory activatory or inhibitory signals through costimulatory receptors. The activatory CD28/B7-1 (or B7-2), inhibitory CTLA4/B7-1 (or B7-2), activatory ICOS/B7H2 and inhibitory PDCD1/B7H1 (or B7DC) pathways involve the interaction of the V-LIKE-DOMAIN of the receptor with a B7 family member. The BTLA/HVEM pathway involves the interaction of the BTLA receptor C-LIKE-DOMAIN with HVEM, a TNFR family member. The human and mouse CD28, CTLA4, ICOS, PDCD1 and BTLA genes, alleles and alternative transcripts and the IMGT Colliers de Perles of the IgSF domains, based on the IMGT unique numbering, are described according to the IMGT-ONTOLOGY concepts of IMGT^®, the international ImMunoGeneTics information system^®, http://imgt.cines.fr).

Introduction

Mounting an appropriate immune response depends on the careful regulation of lymphocyte activation. Lymphocytes require two independent signals to become fully activated. The first one is an antigen-specific signal. The T cell receptors (TR) on T cells or the immunoglobulins (IG) on B cells specifically bind the antigen and the signal is transmitted to the cell interior through the coreceptors which comprise for the TR the CD3 gamma (CD3G), CD3 delta (CD3D), CD3 epsilon (CD3E) and alternatively spliced CD3 zeta and CD3 eta (CD3Z) proteins organized in CD3γε, δε, and ζζ or ζη dimers, and for the IG, CD79A and CD79B [1], [2]. A second signal, termed ‘costimulation’ is critical for full activation of a naive lymphocyte. The costimulatory signal is independent of the antigen receptor and has no stimulatory capacity on its own, but is required to allow full activation [3].

The first cell surface protein shown to function as a costimulatory receptor on T lymphocytes was CD28 [4]. Since the identification of CD28, the number of proposed costimulatory receptors has grown significantly [5]. They are classified into activatory and inhibitory receptors depending on the resulting positive or negative signal on T cell activation, which follows ligand binding. These proteins possess at least one domain with a V-LIKE or C-LIKE fold and thus belong to the immunoglobulin superfamily (IgSF) [6], [7], [8] (Table 1). They are type I transmembrane proteins.

The CD28 family includes three closely related members: CD28, CTLA4 (cytotoxic T-lymphocyte-associated protein 4) and ICOS (inducible T cell costimulator). Programmed cell death 1 (PDCD1) represents a more distantly related protein. The extracellular region of the CD28 family member (CD28, CTLA4, ICOS) proteins and of the PDCD1 protein comprises one V-LIKE-DOMAIN [9]. Their ligands expressed on antigen-presenting cells (APC) are members of the B7 family [10], [11]. CD28, an activatory receptor [4], [12], and CTLA4, an inhibitory receptor [13], [14], [15], share the same ligands B7-1 (CD80) and B7-2 (CD86) [16], [17]. ICOS, an activatory receptor [18], [19] binds B7H2 (ICOSL, B7RP1) [20], [21]. PDCD1, an inhibitory receptor [22], binds B7H1 (PD-L1, B7-H1) and B7DC (PD-L2, B7-DC) [23]. A fifth receptor, B and T lymphocyte attenuator (BTLA) comprises one C-LIKE-DOMAIN [9]. BTLA, an inhibitory receptor, binds herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily [24], [25], [26] although it was first suggested that it may also interact with B7H4 [27]. The costimulatory receptors bind their ligands via their extracellular IgSF domain (V-LIKE-DOMAIN for CD28, CTLA4, ICOS and PDCD1 and C-LIKE-DOMAIN for BTLA) and the signal is exerted and delivered to the T cells through the cytoplasmic region of the receptors.

In humans, the CD28, CTLA4, ICOS and PDCD1 genes are localized on chromosome 2 (Table 2, Fig. 1). The CD28, CTLA4 and ICOS genes are closely linked at 2q33.3 and oriented in the forward (FWD) orientation [28], [29]. They form an immunological costimulatory receptor locus which spans 380 kilobases (kb). CD28 and CTLA4 are separated by 30 kb [30]. Human chromosome 2q33 is considered as an immunologically important region based on the linkage of numerous autoimmune diseases to the CTLA4 locus [31]. PDCD1 is localized on chromosome 2 at 2q37.3 [32] and BTLA on chromosome 3 at 3q13.2, both genes being in reverse (REV) orientation [24].

In this review, we provide a standardized description of the human and mouse CD28, CTLA4, ICOS, PDCD1 and BTLA genes and proteins according to IMGT-ONTOLOGY [33] and to the IMGT Scientific chart rules [34], [35], [36]. We provide two-dimensional (2D) graphical representations or IMGT Collier de Perles of the IgSF domains based on the IMGT unique numbering [6], [7]. The IMGT Colliers de Perles allow to bridge the gap between sequences and 3D structures in IMGT^®, the international ImMunoGeneTics information system^® [34], as this can be demonstrated with the three-dimensional (3D) structures for CD28, CTLA4, PDCD1 and BTLA, which are available in PDB [37] and in IMGT/3Dstructure-DB [38]. The IMGT Colliers de Perles also allow to compare IgSF domains between non-mammalian species as recently shown in teleost [9].