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Quantitative contribution of CD4 and CD8 to T cell antigen receptor serial triggering.

Viola A, Salio M, Tuosto L, Linkert S, Acuto O, Lanzavecchia A - J. Exp. Med. (1997)

Bottom Line: This coordinated disappearance takes place whenever the TCR is triggered, even when the coreceptor does not engage the cognate MHC molecule and is the consequence of binding of the coreceptor-associated Lck to ZAP-70.The interaction of coreceptor and cognate MHC molecules is dispensable when T cells are stimulated by optimal ligands, but becomes crucial when suboptimal ligands are used.In the latter case the coreceptor increases the efficiency of TCR triggering without changing the activation threshold or the quality of the T cell response.

View Article: PubMed Central - PubMed

Affiliation: Basel Institute for Immunology, Switzerland. viola@bii.ch

ABSTRACT
CD4 and CD8 are thought to function as coreceptors by binding to the cognate major histocompatibility complex (MHC) molecules recognized by the T cell antigen receptor (TCR) and initiating the signal transduction cascade. We report that during T cell-antigen-presenting cell interaction, triggered TCRs and coreceptors are downregulated and degraded with identical kinetics. This coordinated disappearance takes place whenever the TCR is triggered, even when the coreceptor does not engage the cognate MHC molecule and is the consequence of binding of the coreceptor-associated Lck to ZAP-70. The interaction of coreceptor and cognate MHC molecules is dispensable when T cells are stimulated by optimal ligands, but becomes crucial when suboptimal ligands are used. In the latter case the coreceptor increases the efficiency of TCR triggering without changing the activation threshold or the quality of the T cell response.

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Parallel downregulation  and degradation of CD4 and CD8 together with CD3 in T cell clones stimulated by specific antigen. (A) Time  course of CD3 (•) and CD4 (▵) downregulation in clone KS140 stimulated  with APCs pulsed with 10 nM TT830-842. (B) CD3 (•) and CD8 (□) downregulation in clone CER22 stimulated  with APCs pulsed with 100 nM M58-66. (C) Surface and total levels of CD3 and CD4 as determined by staining before and after permeabilization in KS70 cells conjugated for 5 h with APCs  unpulsed (empty bars) or pulsed with 0.1 μM (hatched bars) or 10 μM (filled bars) TT830-842.
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Figure 1: Parallel downregulation and degradation of CD4 and CD8 together with CD3 in T cell clones stimulated by specific antigen. (A) Time course of CD3 (•) and CD4 (▵) downregulation in clone KS140 stimulated with APCs pulsed with 10 nM TT830-842. (B) CD3 (•) and CD8 (□) downregulation in clone CER22 stimulated with APCs pulsed with 100 nM M58-66. (C) Surface and total levels of CD3 and CD4 as determined by staining before and after permeabilization in KS70 cells conjugated for 5 h with APCs unpulsed (empty bars) or pulsed with 0.1 μM (hatched bars) or 10 μM (filled bars) TT830-842.

Mentions: To understand the contribution of the coreceptor to TCR triggering and T cell activation, we studied the TCR–coreceptor interaction in T cells stimulated by a specific ligand. It has been shown that, after triggering by agonists, TCRs are downregulated and degraded and this downregulation can be used to measure the number of TCRs triggered (17, 18). Therefore, we investigated whether the CD4 or CD8 coreceptors would also be downregulated together with the TCR. We observed that in specific T–APC conjugates, TCRs and coreceptors are downregulated with the same kinetics and with fixed stoichiometry (Fig. 1, A and B). In addition, downregulation is followed by rapid degradation of both coreceptor and TCR (Fig. 1 C). By reference to a standard curve of Ig-coated beads, we estimated that approximately two CD4 or four CD8 molecules are downregulated for each TCR (data not shown), an estimate which is consistent with that reported for CD4 by Saizawa and Janeway (24).


Quantitative contribution of CD4 and CD8 to T cell antigen receptor serial triggering.

Viola A, Salio M, Tuosto L, Linkert S, Acuto O, Lanzavecchia A - J. Exp. Med. (1997)

Parallel downregulation  and degradation of CD4 and CD8 together with CD3 in T cell clones stimulated by specific antigen. (A) Time  course of CD3 (•) and CD4 (▵) downregulation in clone KS140 stimulated  with APCs pulsed with 10 nM TT830-842. (B) CD3 (•) and CD8 (□) downregulation in clone CER22 stimulated  with APCs pulsed with 100 nM M58-66. (C) Surface and total levels of CD3 and CD4 as determined by staining before and after permeabilization in KS70 cells conjugated for 5 h with APCs  unpulsed (empty bars) or pulsed with 0.1 μM (hatched bars) or 10 μM (filled bars) TT830-842.
© Copyright Policy
Related In: Results  -  Collection

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Figure 1: Parallel downregulation and degradation of CD4 and CD8 together with CD3 in T cell clones stimulated by specific antigen. (A) Time course of CD3 (•) and CD4 (▵) downregulation in clone KS140 stimulated with APCs pulsed with 10 nM TT830-842. (B) CD3 (•) and CD8 (□) downregulation in clone CER22 stimulated with APCs pulsed with 100 nM M58-66. (C) Surface and total levels of CD3 and CD4 as determined by staining before and after permeabilization in KS70 cells conjugated for 5 h with APCs unpulsed (empty bars) or pulsed with 0.1 μM (hatched bars) or 10 μM (filled bars) TT830-842.
Mentions: To understand the contribution of the coreceptor to TCR triggering and T cell activation, we studied the TCR–coreceptor interaction in T cells stimulated by a specific ligand. It has been shown that, after triggering by agonists, TCRs are downregulated and degraded and this downregulation can be used to measure the number of TCRs triggered (17, 18). Therefore, we investigated whether the CD4 or CD8 coreceptors would also be downregulated together with the TCR. We observed that in specific T–APC conjugates, TCRs and coreceptors are downregulated with the same kinetics and with fixed stoichiometry (Fig. 1, A and B). In addition, downregulation is followed by rapid degradation of both coreceptor and TCR (Fig. 1 C). By reference to a standard curve of Ig-coated beads, we estimated that approximately two CD4 or four CD8 molecules are downregulated for each TCR (data not shown), an estimate which is consistent with that reported for CD4 by Saizawa and Janeway (24).

Bottom Line: This coordinated disappearance takes place whenever the TCR is triggered, even when the coreceptor does not engage the cognate MHC molecule and is the consequence of binding of the coreceptor-associated Lck to ZAP-70.The interaction of coreceptor and cognate MHC molecules is dispensable when T cells are stimulated by optimal ligands, but becomes crucial when suboptimal ligands are used.In the latter case the coreceptor increases the efficiency of TCR triggering without changing the activation threshold or the quality of the T cell response.

View Article: PubMed Central - PubMed

Affiliation: Basel Institute for Immunology, Switzerland. viola@bii.ch

ABSTRACT
CD4 and CD8 are thought to function as coreceptors by binding to the cognate major histocompatibility complex (MHC) molecules recognized by the T cell antigen receptor (TCR) and initiating the signal transduction cascade. We report that during T cell-antigen-presenting cell interaction, triggered TCRs and coreceptors are downregulated and degraded with identical kinetics. This coordinated disappearance takes place whenever the TCR is triggered, even when the coreceptor does not engage the cognate MHC molecule and is the consequence of binding of the coreceptor-associated Lck to ZAP-70. The interaction of coreceptor and cognate MHC molecules is dispensable when T cells are stimulated by optimal ligands, but becomes crucial when suboptimal ligands are used. In the latter case the coreceptor increases the efficiency of TCR triggering without changing the activation threshold or the quality of the T cell response.

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