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Dependence of T cell antigen recognition on the dimensions of an accessory receptor-ligand complex.

Wild MK, Cambiaggi A, Brown MH, Davies EA, Ohno H, Saito T, van der Merwe PA - J. Exp. Med. (1999)

Bottom Line: The T cell antigen receptor (TCR) and its ligand peptide-major histocompatibility complex (MHC) are small (approximately 7 nm) compared with other abundant cell surface molecules such as integrins, CD43, and CD45 (23-50 nm).Immunol.Today. 17:177-187).

View Article: PubMed Central - PubMed

Affiliation: Sir William Dunn School of Pathology, University of Oxford, United Kingdom.

ABSTRACT
The T cell antigen receptor (TCR) and its ligand peptide-major histocompatibility complex (MHC) are small (approximately 7 nm) compared with other abundant cell surface molecules such as integrins, CD43, and CD45 (23-50 nm). We have proposed that molecules at the T cell/antigen-presenting cell (APC) interface segregate according to size, with small "accessory" molecules (e.g., CD2, CD4, CD8, CD28, and CD154) contributing to the formation of a close-contact zone, within which the TCR engages peptide-MHC, and from which large molecules are excluded (Davis, S.J., and P.A. van der Merwe. 1996. Immunol. Today. 17:177-187). One prediction of this model is that increasing the size of these small accessory molecules will disrupt their function. Here, we test this prediction by varying the dimensions of the CD2 ligand, CD48, and examining how this affects T cell antigen recognition. Although the interaction of CD2 on T cells with wild-type or shortened forms of CD48 on APCs enhances T cell antigen recognition, the interaction of CD2 with elongated forms of CD48 is strongly inhibitory. Further experiments indicated that elongation of the CD2/CD48 complex inhibited TCR engagement of peptide-MHC, presumably by preventing the formation of sufficiently intimate contacts at the T cell/APC interface. These findings demonstrate the importance of small size in CD2/CD48 function, and support the hypothesis that T cell antigen recognition requires segregation of cell surface molecules according to size.

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A shortened form of CD48 is able to enhance T cell antigen recognition. Assay performed as in the legend to Fig. 3 A using as responders 2B4 cells expressing either full-length (2B4.CD2) or truncated (2B4.CD2trunc) forms of CD2, and as APCs I-Ek+ CHO cells expressing no CD48 (CD48 neg CHO), wild-type CD48, or shortened CD48 (CD48d1 CHO).
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Figure 6: A shortened form of CD48 is able to enhance T cell antigen recognition. Assay performed as in the legend to Fig. 3 A using as responders 2B4 cells expressing either full-length (2B4.CD2) or truncated (2B4.CD2trunc) forms of CD2, and as APCs I-Ek+ CHO cells expressing no CD48 (CD48 neg CHO), wild-type CD48, or shortened CD48 (CD48d1 CHO).

Mentions: We next examined the effect of shortening CD48. Because CD48 has only two Ig domains, it was only possible to shorten it by a single domain (∼3.5 nm). In contrast to the long forms of CD48, transfection of I-Ek+ CHO with a shortened form of CD48 (CD48d1; Fig. 1 A) enhanced peptide–MHC-induced activation of 2B4 (Fig. 6). Enhancement by CD48d1 was observed with 2B4 cells expressing both full-length (Fig. 6 A) and truncated (Fig. 6 B) CD2, but was somewhat reduced compared with wild-type CD48 (Fig. 6). Because the surface expression of CD48d1 was only half that of CD48 (Fig. 2 B), and CD2 binding to these cells was also substantially reduced (Fig. 2 B), it is not possible to deduce from these data how much less effective CD48d1 is than full-length CD48 at enhancing T cell antigen recognition. Nevertheless, it is clear that shortening of CD48 does not have the same inhibitory effect as elongation. This is an important control, since both shortening and elongation of CD48 would be expected to disrupt cis-interactions with other surface molecules. It follows that elongation of CD48 cannot be inhibiting by disrupting such cis-interactions.


Dependence of T cell antigen recognition on the dimensions of an accessory receptor-ligand complex.

Wild MK, Cambiaggi A, Brown MH, Davies EA, Ohno H, Saito T, van der Merwe PA - J. Exp. Med. (1999)

A shortened form of CD48 is able to enhance T cell antigen recognition. Assay performed as in the legend to Fig. 3 A using as responders 2B4 cells expressing either full-length (2B4.CD2) or truncated (2B4.CD2trunc) forms of CD2, and as APCs I-Ek+ CHO cells expressing no CD48 (CD48 neg CHO), wild-type CD48, or shortened CD48 (CD48d1 CHO).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195552&req=5

Figure 6: A shortened form of CD48 is able to enhance T cell antigen recognition. Assay performed as in the legend to Fig. 3 A using as responders 2B4 cells expressing either full-length (2B4.CD2) or truncated (2B4.CD2trunc) forms of CD2, and as APCs I-Ek+ CHO cells expressing no CD48 (CD48 neg CHO), wild-type CD48, or shortened CD48 (CD48d1 CHO).
Mentions: We next examined the effect of shortening CD48. Because CD48 has only two Ig domains, it was only possible to shorten it by a single domain (∼3.5 nm). In contrast to the long forms of CD48, transfection of I-Ek+ CHO with a shortened form of CD48 (CD48d1; Fig. 1 A) enhanced peptide–MHC-induced activation of 2B4 (Fig. 6). Enhancement by CD48d1 was observed with 2B4 cells expressing both full-length (Fig. 6 A) and truncated (Fig. 6 B) CD2, but was somewhat reduced compared with wild-type CD48 (Fig. 6). Because the surface expression of CD48d1 was only half that of CD48 (Fig. 2 B), and CD2 binding to these cells was also substantially reduced (Fig. 2 B), it is not possible to deduce from these data how much less effective CD48d1 is than full-length CD48 at enhancing T cell antigen recognition. Nevertheless, it is clear that shortening of CD48 does not have the same inhibitory effect as elongation. This is an important control, since both shortening and elongation of CD48 would be expected to disrupt cis-interactions with other surface molecules. It follows that elongation of CD48 cannot be inhibiting by disrupting such cis-interactions.

Bottom Line: The T cell antigen receptor (TCR) and its ligand peptide-major histocompatibility complex (MHC) are small (approximately 7 nm) compared with other abundant cell surface molecules such as integrins, CD43, and CD45 (23-50 nm).Immunol.Today. 17:177-187).

View Article: PubMed Central - PubMed

Affiliation: Sir William Dunn School of Pathology, University of Oxford, United Kingdom.

ABSTRACT
The T cell antigen receptor (TCR) and its ligand peptide-major histocompatibility complex (MHC) are small (approximately 7 nm) compared with other abundant cell surface molecules such as integrins, CD43, and CD45 (23-50 nm). We have proposed that molecules at the T cell/antigen-presenting cell (APC) interface segregate according to size, with small "accessory" molecules (e.g., CD2, CD4, CD8, CD28, and CD154) contributing to the formation of a close-contact zone, within which the TCR engages peptide-MHC, and from which large molecules are excluded (Davis, S.J., and P.A. van der Merwe. 1996. Immunol. Today. 17:177-187). One prediction of this model is that increasing the size of these small accessory molecules will disrupt their function. Here, we test this prediction by varying the dimensions of the CD2 ligand, CD48, and examining how this affects T cell antigen recognition. Although the interaction of CD2 on T cells with wild-type or shortened forms of CD48 on APCs enhances T cell antigen recognition, the interaction of CD2 with elongated forms of CD48 is strongly inhibitory. Further experiments indicated that elongation of the CD2/CD48 complex inhibited TCR engagement of peptide-MHC, presumably by preventing the formation of sufficiently intimate contacts at the T cell/APC interface. These findings demonstrate the importance of small size in CD2/CD48 function, and support the hypothesis that T cell antigen recognition requires segregation of cell surface molecules according to size.

Show MeSH
Related in: MedlinePlus