Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 1, Pages 47-61Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.1.47
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Funding
- NCI NIH HHS [R01 CA095572-06, R01 CA95572, R01 CA095572] Funding Source: Medline
- NIAID NIH HHS [R01 AI047466, R01 AI047466-07A2] Funding Source: Medline
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CD40/CD40L signaling promotes both B cell and CTL responses in vivo, the latter being beneficial in tumor models. Because CTL may also limit autoreactive B cell expansion in lupus, we asked whether an agonist CD40 mAb would exacerbate Inputs due to B cell stimulation or would improve lupus due to CTL promotion. These studies' used an induced model of lupus, the parent-into-F-1, model in which transfer of DBA/2 splenocytes into B6D2F(1) mice induces chronic lupus-like graft-vs-host disease (GVHD). Although agonist CD40 mAb treatment of DBA -> F-1 mice initially exacerbated B cell expansion, it also strongly prompted donor CD8 T cell engraftment and cytolytic activity such that by 10 days host B cells were eliminated consistent with an accelerated acute GVHD. CD40 stimulation bypassed the requirement for CD4 T cell help for CD8 CTL possibly by licensing dendritic cells (DC) as shown by the following: 1) greater initial activation of donor CD8 T cells, but not CD4 T cells;;) earlier activation of host DC; 3) host DC expansion that was CD8 dependent and CD4 independent; and 4) induction of acute GVHD using CD4-depleted purified DBA CD8(+) T cells. A single dose of CD40 mAb improved lupus-like renal disease at 12 wk, but may not suffice for longer periods consistent with a need for continuing CD8 CTL surveillance. These results demonstrate that in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, CTL promotion is both feasible and beneficial and the CTL-promoting properties of CD40 stimulation outweigh the B cell-stimulatory properties.
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