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Sensory adaptation in naive peripheral CD4 T cells.

Smith K, Seddon B, Purbhoo MA, Zamoyska R, Fisher AG, Merkenschlager M - J. Exp. Med. (2001)

Bottom Line: Here we show that pMHC contact modulates the expression of CD5 by naive CD4 T cells in a process that requires the continued expression of p56(lck).Reduced CD5 levels in T cells deprived of pMHC contact are predictive of elevated Ca(2)+ responses to subsequent TCR engagement by anti-CD3 or nominal antigen.Adaptation to peripheral pMHC contact may be important for regulating naive CD4 T cell responsiveness.

View Article: PubMed Central - PubMed

Affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, ICSM Hammersmith Hospital, London W12 0NN, UK.

ABSTRACT
T cell receptor interactions with peptide/major histocompatibility complex (pMHC) ligands control the selection of T cells in the thymus as well as their homeostasis in peripheral lymphoid organs. Here we show that pMHC contact modulates the expression of CD5 by naive CD4 T cells in a process that requires the continued expression of p56(lck). Reduced CD5 levels in T cells deprived of pMHC contact are predictive of elevated Ca(2)+ responses to subsequent TCR engagement by anti-CD3 or nominal antigen. Adaptation to peripheral pMHC contact may be important for regulating naive CD4 T cell responsiveness.

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Polyclonal CD5low CD4 LN cells show impaired MHC-dependent homeostatic expansion relative to their CD5high counterparts. Polyclonal LN cells were separated into CD4+CD44lowCD5low and CD4+CD44low CD5high populations by cell sorting as in Fig. 6 A. After labeling with CFSE 1–4 × 106 cells of each population were adoptively transferred into sublethally irradiated syngeneic hosts. Proliferation was recorded as reduced CFSE fluorescence intensity 9 d later. Displays are gated on CD4+ CFSE+ cells. The percentage of undivided cells is indicated.
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fig7: Polyclonal CD5low CD4 LN cells show impaired MHC-dependent homeostatic expansion relative to their CD5high counterparts. Polyclonal LN cells were separated into CD4+CD44lowCD5low and CD4+CD44low CD5high populations by cell sorting as in Fig. 6 A. After labeling with CFSE 1–4 × 106 cells of each population were adoptively transferred into sublethally irradiated syngeneic hosts. Proliferation was recorded as reduced CFSE fluorescence intensity 9 d later. Displays are gated on CD4+ CFSE+ cells. The percentage of undivided cells is indicated.

Mentions: Hence, as shown above for AND T cells deprived of pMHC interactions, CD5 expression is predictive of responsiveness to anti-CD3 also in polyclonal naive CD4 T cells. We performed adoptive transfer experiments to investigate the role of MHC interactions in the regulation of CD5 expression in polyclonal CD4 T cells and to compare the ability of the CD44lowCD5low and CD44lowCD5high subsets to proliferate in sublethally irradiated syngeneic hosts or Rag-1o/o MHCo/o mice. As a test for their ability to engage in productive interactions with syngeneic pMHC ligands 30–32, 35) sorted CD4+ CD44low CD5high and CD5low populations of C57Bl/10 or Balb/c LN cells were labeled with CFSE and transferred into sublethally (450 rad) irradiated syngeneic hosts. 9–12 d after transfer LN and spleens were recovered and donor cells identified as CFSE+ CD4+. Both populations had maintained their initial CD5 levels (Table I). Analysis of cell division, quantitated as the dilution of CFSE, showed that only a minority of 20–25% of CD5high cells remained undivided whereas in excess of 50% of CD5low cells had failed to divide (Fig. 7 , Table I). The observation that CD5low cells proliferate poorly to syngeneic pMHC contact despite their elevated responsiveness to CD3-mediated receptor ligation (Figs. 5 and 6) might at first seem counterintuitive but is in fact predicted if, as suggested by the data in Figs. 2 and 4, low CD5 levels reflect poor self-pMHC interactions (see Discussion). We controlled for the possibility that the different rates of division after transfer into syngeneic hosts were due to underlying differences in the proliferative response of CD5high and CD5low naive CD4 T cells to MHC-independent factors in highly lymphopenic hosts (45, 46) by transfer of CD5high and CD5low naive CD4 T cells into Rag-1o/o MHCo/o mice. In this setting both populations responded with comparable rates of proliferation and CD5 expression by both populations was reduced two to threefold (Table I). Hence, deprivation from pMHC interactions results in reduced CD5 expression in polyclonal naive CD4 T cells. Consistent with a role for pMHC interactions in regulating CD5 expression by naive polyclonal CD4 T cells, the CD5low fraction of the naive CD4 T cell repertoire has limited ability to interact productively with syngeneic pMHC as measured by homeostatic proliferation in syngeneic hosts.


Sensory adaptation in naive peripheral CD4 T cells.

Smith K, Seddon B, Purbhoo MA, Zamoyska R, Fisher AG, Merkenschlager M - J. Exp. Med. (2001)

Polyclonal CD5low CD4 LN cells show impaired MHC-dependent homeostatic expansion relative to their CD5high counterparts. Polyclonal LN cells were separated into CD4+CD44lowCD5low and CD4+CD44low CD5high populations by cell sorting as in Fig. 6 A. After labeling with CFSE 1–4 × 106 cells of each population were adoptively transferred into sublethally irradiated syngeneic hosts. Proliferation was recorded as reduced CFSE fluorescence intensity 9 d later. Displays are gated on CD4+ CFSE+ cells. The percentage of undivided cells is indicated.
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Related In: Results  -  Collection

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fig7: Polyclonal CD5low CD4 LN cells show impaired MHC-dependent homeostatic expansion relative to their CD5high counterparts. Polyclonal LN cells were separated into CD4+CD44lowCD5low and CD4+CD44low CD5high populations by cell sorting as in Fig. 6 A. After labeling with CFSE 1–4 × 106 cells of each population were adoptively transferred into sublethally irradiated syngeneic hosts. Proliferation was recorded as reduced CFSE fluorescence intensity 9 d later. Displays are gated on CD4+ CFSE+ cells. The percentage of undivided cells is indicated.
Mentions: Hence, as shown above for AND T cells deprived of pMHC interactions, CD5 expression is predictive of responsiveness to anti-CD3 also in polyclonal naive CD4 T cells. We performed adoptive transfer experiments to investigate the role of MHC interactions in the regulation of CD5 expression in polyclonal CD4 T cells and to compare the ability of the CD44lowCD5low and CD44lowCD5high subsets to proliferate in sublethally irradiated syngeneic hosts or Rag-1o/o MHCo/o mice. As a test for their ability to engage in productive interactions with syngeneic pMHC ligands 30–32, 35) sorted CD4+ CD44low CD5high and CD5low populations of C57Bl/10 or Balb/c LN cells were labeled with CFSE and transferred into sublethally (450 rad) irradiated syngeneic hosts. 9–12 d after transfer LN and spleens were recovered and donor cells identified as CFSE+ CD4+. Both populations had maintained their initial CD5 levels (Table I). Analysis of cell division, quantitated as the dilution of CFSE, showed that only a minority of 20–25% of CD5high cells remained undivided whereas in excess of 50% of CD5low cells had failed to divide (Fig. 7 , Table I). The observation that CD5low cells proliferate poorly to syngeneic pMHC contact despite their elevated responsiveness to CD3-mediated receptor ligation (Figs. 5 and 6) might at first seem counterintuitive but is in fact predicted if, as suggested by the data in Figs. 2 and 4, low CD5 levels reflect poor self-pMHC interactions (see Discussion). We controlled for the possibility that the different rates of division after transfer into syngeneic hosts were due to underlying differences in the proliferative response of CD5high and CD5low naive CD4 T cells to MHC-independent factors in highly lymphopenic hosts (45, 46) by transfer of CD5high and CD5low naive CD4 T cells into Rag-1o/o MHCo/o mice. In this setting both populations responded with comparable rates of proliferation and CD5 expression by both populations was reduced two to threefold (Table I). Hence, deprivation from pMHC interactions results in reduced CD5 expression in polyclonal naive CD4 T cells. Consistent with a role for pMHC interactions in regulating CD5 expression by naive polyclonal CD4 T cells, the CD5low fraction of the naive CD4 T cell repertoire has limited ability to interact productively with syngeneic pMHC as measured by homeostatic proliferation in syngeneic hosts.

Bottom Line: Here we show that pMHC contact modulates the expression of CD5 by naive CD4 T cells in a process that requires the continued expression of p56(lck).Reduced CD5 levels in T cells deprived of pMHC contact are predictive of elevated Ca(2)+ responses to subsequent TCR engagement by anti-CD3 or nominal antigen.Adaptation to peripheral pMHC contact may be important for regulating naive CD4 T cell responsiveness.

View Article: PubMed Central - PubMed

Affiliation: Lymphocyte Development Group, MRC Clinical Sciences Centre, ICSM Hammersmith Hospital, London W12 0NN, UK.

ABSTRACT
T cell receptor interactions with peptide/major histocompatibility complex (pMHC) ligands control the selection of T cells in the thymus as well as their homeostasis in peripheral lymphoid organs. Here we show that pMHC contact modulates the expression of CD5 by naive CD4 T cells in a process that requires the continued expression of p56(lck). Reduced CD5 levels in T cells deprived of pMHC contact are predictive of elevated Ca(2)+ responses to subsequent TCR engagement by anti-CD3 or nominal antigen. Adaptation to peripheral pMHC contact may be important for regulating naive CD4 T cell responsiveness.

Show MeSH