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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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Quantitative contribution of CD4 to TCR triggering and T cell activation. (A)  IFN-γ production by T cell  clone AL15.1 stimulated by  TT830-843 (•, ○) or by  TT830-843 Gln839 (▴, ▵) in the  presence (•,▴) or absence (○,  ▵) of anti-CD4 antibody. (B)  CD3 downregulation in the  same experiment. (C–E) Levels  of IFN-γ (▴), IL-2 (•), TNF-α  (▪), and IL-3 (▵) as a function  of the number of TCRs downregulated in cultures stimulated  by wild-type agonist (C), wild-type agonist + anti-CD4 (D), or  weak agonist (E). No cytokine  production was observed in cultures stimulated by weak agonist  + anti-CD4.
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Figure 5: Quantitative contribution of CD4 to TCR triggering and T cell activation. (A) IFN-γ production by T cell clone AL15.1 stimulated by TT830-843 (•, ○) or by TT830-843 Gln839 (▴, ▵) in the presence (•,▴) or absence (○, ▵) of anti-CD4 antibody. (B) CD3 downregulation in the same experiment. (C–E) Levels of IFN-γ (▴), IL-2 (•), TNF-α (▪), and IL-3 (▵) as a function of the number of TCRs downregulated in cultures stimulated by wild-type agonist (C), wild-type agonist + anti-CD4 (D), or weak agonist (E). No cytokine production was observed in cultures stimulated by weak agonist + anti-CD4.

Mentions: To investigate whether the lower response of T cells in the presence of anti-CD4 antibodies reflects a lower extent of TCR triggering or, rather, an altered signal leading to qualitatively different responses, we correlated TCR downregulation and cytokine production in T cells stimulated by strong or weak agonists in the presence or absence of anti-CD4 antibodies. As shown in Fig. 5, the inhibition of T cell response by anti-CD4 antibodies precisely correlated with a reduced level of TCR downregulation both when strong and weak agonists were used. These results indicate that the anti-CD4 antibody mimics the effect of a weak agonist, i.e., results in a decreased efficiency of serial triggering. However, in spite of a decreased efficiency of TCR triggering, the threshold of T cell activation and the type of cytokines produced were not affected by anti-CD4. Indeed, T cells produced IFN-γ, IL-2, and TNF-α when ∼20–30% of TCRs were triggered, irrespective of the strength of the agonist and of the presence or absence of anti-CD4. IL-3 production consistently required higher levels of TCR occupancy, which were comparable in all experimental conditions.


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)

Quantitative contribution of CD4 to TCR triggering and T cell activation. (A)  IFN-γ production by T cell  clone AL15.1 stimulated by  TT830-843 (•, ○) or by  TT830-843 Gln839 (▴, ▵) in the  presence (•,▴) or absence (○,  ▵) of anti-CD4 antibody. (B)  CD3 downregulation in the  same experiment. (C–E) Levels  of IFN-γ (▴), IL-2 (•), TNF-α  (▪), and IL-3 (▵) as a function  of the number of TCRs downregulated in cultures stimulated  by wild-type agonist (C), wild-type agonist + anti-CD4 (D), or  weak agonist (E). No cytokine  production was observed in cultures stimulated by weak agonist  + anti-CD4.
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Related In: Results  -  Collection

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Figure 5: Quantitative contribution of CD4 to TCR triggering and T cell activation. (A) IFN-γ production by T cell clone AL15.1 stimulated by TT830-843 (•, ○) or by TT830-843 Gln839 (▴, ▵) in the presence (•,▴) or absence (○, ▵) of anti-CD4 antibody. (B) CD3 downregulation in the same experiment. (C–E) Levels of IFN-γ (▴), IL-2 (•), TNF-α (▪), and IL-3 (▵) as a function of the number of TCRs downregulated in cultures stimulated by wild-type agonist (C), wild-type agonist + anti-CD4 (D), or weak agonist (E). No cytokine production was observed in cultures stimulated by weak agonist + anti-CD4.
Mentions: To investigate whether the lower response of T cells in the presence of anti-CD4 antibodies reflects a lower extent of TCR triggering or, rather, an altered signal leading to qualitatively different responses, we correlated TCR downregulation and cytokine production in T cells stimulated by strong or weak agonists in the presence or absence of anti-CD4 antibodies. As shown in Fig. 5, the inhibition of T cell response by anti-CD4 antibodies precisely correlated with a reduced level of TCR downregulation both when strong and weak agonists were used. These results indicate that the anti-CD4 antibody mimics the effect of a weak agonist, i.e., results in a decreased efficiency of serial triggering. However, in spite of a decreased efficiency of TCR triggering, the threshold of T cell activation and the type of cytokines produced were not affected by anti-CD4. Indeed, T cells produced IFN-γ, IL-2, and TNF-α when ∼20–30% of TCRs were triggered, irrespective of the strength of the agonist and of the presence or absence of anti-CD4. IL-3 production consistently required higher levels of TCR occupancy, which were comparable in all experimental conditions.

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.

Show MeSH
Related in: MedlinePlus