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Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help.

Bennett SR, Carbone FR, Karamalis F, Miller JF, Heath WR - J. Exp. Med. (1997)

Bottom Line: The related effect of cross-tolerance can also effectively eliminate responses to selected self components.Importantly, this CD4+ population is only effective when both the helper and CTL determinants are recognized on the same APC.Moreover, we would argue that the cognitive nature of this event suggests that the CD4+ T cell actively modifies the APC, converting it into an effective stimulator for the successful priming of the CTL precursor.

View Article: PubMed Central - PubMed

Affiliation: Thymus Biology Unit, The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.

ABSTRACT
Class I-restricted presentation is usually associated with cytoplasmic degradation of cellular proteins and is often considered inaccessible to exogenous antigens. Nonetheless, certain exogenous elements can gain entry into this so-called endogenous pathway by a mechanism termed cross-presentation. This is known to be effective for class I-restricted cytotoxic T lymphocyte (CTL) cross-priming directed against a variety of exogenous tumor, viral, and minor transplantation antigens. The related effect of cross-tolerance can also effectively eliminate responses to selected self components. In both cases, this presentation appears to require the active involvement of a bone marrow-derived antigen presenting cell (APC). Here, we show that CTL induction by cross-priming with cell-associated ovalbumin requires the active involvement of CD4+ helper T cells. Importantly, this CD4+ population is only effective when both the helper and CTL determinants are recognized on the same APC. Moreover, we would argue that the cognitive nature of this event suggests that the CD4+ T cell actively modifies the APC, converting it into an effective stimulator for the successful priming of the CTL precursor.

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OVA-specific cross-presentation requires cognate CD4+ T  cell help. (B6 × bm1)F1 mice were lethally irradiated and reconstituted  with either equal parts of H-2A−/− (class II–deficient) and bm1 bone  marrow (a and c) or (B6 × bm1)F1 bone marrow alone (b). 8 wk later,  these mice were immunized with 2.0 × 107 OVA-loaded bm1 spleen  cells intravenously (a and b) or 10 μg OVA257-264 in 100 μl CFA subcutaneously (c). After 1 wk, their spleen cells were stimulated in vitro for 6 d  and a chromium release assay using OVA257-264-pulsed EL4 (closed symbols)  and EL4 (open symbols) targets was performed. This experiment was performed twice with 2–3 mice/group.
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Figure 5: OVA-specific cross-presentation requires cognate CD4+ T cell help. (B6 × bm1)F1 mice were lethally irradiated and reconstituted with either equal parts of H-2A−/− (class II–deficient) and bm1 bone marrow (a and c) or (B6 × bm1)F1 bone marrow alone (b). 8 wk later, these mice were immunized with 2.0 × 107 OVA-loaded bm1 spleen cells intravenously (a and b) or 10 μg OVA257-264 in 100 μl CFA subcutaneously (c). After 1 wk, their spleen cells were stimulated in vitro for 6 d and a chromium release assay using OVA257-264-pulsed EL4 (closed symbols) and EL4 (open symbols) targets was performed. This experiment was performed twice with 2–3 mice/group.

Mentions: To investigate the basis of CD4+ T cell help, we asked whether CD4+ and CD8+ T cells had to see OVA on the same APC. (B6 × bm1)F1 mice were reconstituted with equal amounts of two types of bone marrow: bm1 bone marrow, and class II knockout B6 bone marrow. This generated a mixture of bm1 APCs that could present OVA to CD4+ but not CD8+ T cells, and class II–deficient APCs that could present OVA to CD8+ but not CD4+ T cells. When these mice were primed with OVA-loaded spleen cells, there was no induction of OVA-specific CTL (Fig. 5 a). This suggested that CD4+ and CD8+ T cells needed to recognize antigen on the same APC. OVA-loaded spleen cell priming used in this experiment was shown to be effective, since it primed for CTL in mice reconstituted with (B6 × bm1)F1 bone marrow, which contain APCs capable of presenting to both CD4+ and CD8+ T cells (Fig. 5 b).


Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help.

Bennett SR, Carbone FR, Karamalis F, Miller JF, Heath WR - J. Exp. Med. (1997)

OVA-specific cross-presentation requires cognate CD4+ T  cell help. (B6 × bm1)F1 mice were lethally irradiated and reconstituted  with either equal parts of H-2A−/− (class II–deficient) and bm1 bone  marrow (a and c) or (B6 × bm1)F1 bone marrow alone (b). 8 wk later,  these mice were immunized with 2.0 × 107 OVA-loaded bm1 spleen  cells intravenously (a and b) or 10 μg OVA257-264 in 100 μl CFA subcutaneously (c). After 1 wk, their spleen cells were stimulated in vitro for 6 d  and a chromium release assay using OVA257-264-pulsed EL4 (closed symbols)  and EL4 (open symbols) targets was performed. This experiment was performed twice with 2–3 mice/group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198964&req=5

Figure 5: OVA-specific cross-presentation requires cognate CD4+ T cell help. (B6 × bm1)F1 mice were lethally irradiated and reconstituted with either equal parts of H-2A−/− (class II–deficient) and bm1 bone marrow (a and c) or (B6 × bm1)F1 bone marrow alone (b). 8 wk later, these mice were immunized with 2.0 × 107 OVA-loaded bm1 spleen cells intravenously (a and b) or 10 μg OVA257-264 in 100 μl CFA subcutaneously (c). After 1 wk, their spleen cells were stimulated in vitro for 6 d and a chromium release assay using OVA257-264-pulsed EL4 (closed symbols) and EL4 (open symbols) targets was performed. This experiment was performed twice with 2–3 mice/group.
Mentions: To investigate the basis of CD4+ T cell help, we asked whether CD4+ and CD8+ T cells had to see OVA on the same APC. (B6 × bm1)F1 mice were reconstituted with equal amounts of two types of bone marrow: bm1 bone marrow, and class II knockout B6 bone marrow. This generated a mixture of bm1 APCs that could present OVA to CD4+ but not CD8+ T cells, and class II–deficient APCs that could present OVA to CD8+ but not CD4+ T cells. When these mice were primed with OVA-loaded spleen cells, there was no induction of OVA-specific CTL (Fig. 5 a). This suggested that CD4+ and CD8+ T cells needed to recognize antigen on the same APC. OVA-loaded spleen cell priming used in this experiment was shown to be effective, since it primed for CTL in mice reconstituted with (B6 × bm1)F1 bone marrow, which contain APCs capable of presenting to both CD4+ and CD8+ T cells (Fig. 5 b).

Bottom Line: The related effect of cross-tolerance can also effectively eliminate responses to selected self components.Importantly, this CD4+ population is only effective when both the helper and CTL determinants are recognized on the same APC.Moreover, we would argue that the cognitive nature of this event suggests that the CD4+ T cell actively modifies the APC, converting it into an effective stimulator for the successful priming of the CTL precursor.

View Article: PubMed Central - PubMed

Affiliation: Thymus Biology Unit, The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.

ABSTRACT
Class I-restricted presentation is usually associated with cytoplasmic degradation of cellular proteins and is often considered inaccessible to exogenous antigens. Nonetheless, certain exogenous elements can gain entry into this so-called endogenous pathway by a mechanism termed cross-presentation. This is known to be effective for class I-restricted cytotoxic T lymphocyte (CTL) cross-priming directed against a variety of exogenous tumor, viral, and minor transplantation antigens. The related effect of cross-tolerance can also effectively eliminate responses to selected self components. In both cases, this presentation appears to require the active involvement of a bone marrow-derived antigen presenting cell (APC). Here, we show that CTL induction by cross-priming with cell-associated ovalbumin requires the active involvement of CD4+ helper T cells. Importantly, this CD4+ population is only effective when both the helper and CTL determinants are recognized on the same APC. Moreover, we would argue that the cognitive nature of this event suggests that the CD4+ T cell actively modifies the APC, converting it into an effective stimulator for the successful priming of the CTL precursor.

Show MeSH
Related in: MedlinePlus