Different superantigens interact with distinct sites in the Vbeta domain of a single T cell receptor.

Abstract

Surntnary CD4 T cell receptors (TCRs) recognize antigenic peptides presented by self major histocompatibility complex (MHC) class II molecules as well as non-self MHC class II molecules. The TCR.s can also recognize endogenous retroviral gene products and bacterial toxins known collectively as superantigens (SAGs) that act mainly on the V{3 gene segment-encoded portion of the V{3 domain; most SAGs also require MHC class II for presentation. We have studied the interaction of the TCR from a well-characterized CD4 T cell line with SAGs by mutational analysis of its VI3 domain. This appears to separate viral (v)SAG from bacterial (b)SAG recognition. T cells having a TCR. with a glycine to valine mutation in amino acid residue 51 (G51V) in complementarity determining region 2 of the TCIL V[3 domain fail to respond the bSAGs staphylococcal entertoxin B (SEB), SEC1, SEC2, and SEC3, whereas they retain the ability to respond to non-self MHC class II molecules and to foreign peptides presented by self MHC class II molecules. It is interesting to note that T cells expressing mutations of both G51V and G53D of V[3 regain the response to SEB and partially that to SEC1, but do not respond to SEC2 and SEC3, suggesting that different bacterial SAGs are viewed differently by the same TCR. These results are surprising, because it has been generally believed that SAG recognition by T cells is mediated exclusively by hypervariable region 4 on the exposed, lateral face of the TCR V[3 domain. Response to the vSAG Mtv-7 was generated by mutation in V[3 residue 24 (N24H), confirming previously published data. These data show that the vSAG Mtv-7 and bSAGs are recognized by different regions of the TCR V[3 domain. In addition, various bSAGs are recognized differently by the same TC1L. Thus, these mutational data, combined with the crystal structure of the TCR ~3 chain, provide evidence for distinct recognition sites for vSAG and bSAG. 1The TC1L can recognize superantigens (SAGs) derived .IL from bacterial or endogenous retroviral genes (bSAG or vSAG). Unlike conventional antigen recognition, where the CDR3 regions of the TCR ~ and [3 chains play a critical role, response to these substances involves primarily the V[3 gene segment-encoded portion of the V[3 domain of the TCR. As 2-10% ofT cells express the product of a given V[3 gene segment, SAGs stimulate T cells of many different specificities. Recognition ofbSAGs and vSAGs by the TCR is believed to involve regions distinct from the antigen recognition site, comprising the CD1L 1, 2, and 3 loops of both chains of the TCR, as predicted earlier (1). Many reports have shown that a region known as hypervariable region 4 (HVR4) between the E and F strands of the TCR. V[3 domain is a crucial site for SAG recognition, but is not 1Abbreviations used in this paper: bSAG, bacterial superantigen; CA, conalbumin; HVR4, hypervariable region 4; SAG, superantigens; SEB, Staphyloccal enterotoxin B; TSST-1, toxic shock syndrome toxin 1. involved in responses to foreign peptide-.self MHC (2-4). Althou...

Chronic sinusitis pathophysiology: The role of allergy

“…50 Superantigens are proteins that bind directly to the major histocompatability complex or ␤-chain of the T-cell receptor, leading to the nonspecific activation of large numbers of T lymphocytes thereby producing a barrage of cytokine secretion. 48 Bacterial-derived superantigen expression can be identified in up to 90% of patients with CS. 8 Because the T cells infiltrating the sinuses of CHES generally display a Th2 cytokine signature, 51 this superantigen-mediated surge in cytokines will include IL-4 and IL-13, production of which will drive any B cells present to synthesize IgE antibodies to any humoral antigen to which that B cell is responding at that moment.…”

“…8,45 These bacteria can drive the recurrent acute infections that plague CS patients, when they transform into their planktonic state and emerge from the biofilm. However, even in their indolent biofilm-associated state, these bacteria are not innocuous and can be a robust source of superantigens, [45][46][47][48][49] immune adjuvants, and of allergenic (IgE inducing) proteins (Fig. 2).…”

Topical Superantigen Exposure Induces Epidermal Accumulation of CD8+ T Cells, a Mixed Th1/Th2-Type Dermatitis and Vigorous Production of IgE Antibodies in the Murine Model of Atopic Dermatitis

“…S. aureus can trigger allergic (9) inflammation by producing exotoxins with superantigenic properties (6). Bacterial superantigens (e.g., staphylococcal enterotoxin A, B, C, and D and toxic shock syndrome toxin-1) activate T cells by cross-linking an outside domain of the MHC class II (MHC II) on APC with the variable portion of the ␤-chain of the TCRV␤-chains (10,11). This does not require internalization and proteolysis, as in the case in conventional Ags.…”

Electrical activity in rat cortico-limbic structures after single or repeated administration of lipopolysaccharide or staphylococcal enterotoxin B

“…IL-1b, IL-6 and TNFa) [25]. In contrast, the superantigen SEB strongly activates T lymphocyte clones via the T-cell receptor (V-b8), concomitantly resulting in increases of IL-2 and other cytokines in the blood [26,27]. The magnitude of the immune response to both antigens largely depends on the individual immune history; in contrast to the robust immune response during the first antigen encounter with pronounced cytokine release, repeated inoculations of LPS or SEB lead to desensitization, significantly dampening peripheral immune responses such as cytokine production [28,29].…”