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*
Department of Surgery, Section of General Surgery, and
Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109;
Department of Inflammation and Autoimmune Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110; and
§
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132
IL-12p70, a 70- to 75-kDa heterodimer consisting of
disulfide-bonded 35-kDa (p35) and 40-kDa (p40) subunits, enhances Th1
development primarily by its ability to induce IFN-
production by NK
and Th1 cells. Although homodimers of the p40 subunit of IL-12 are
potent IL-12 receptor antagonists in some systems, we have reported
that p40 homodimer may accentuate alloreactive CD8+
Th1 function. To test the role of endogenously produced p40 in
alloimmunity, Th1 development was assessed in either IL-12 p35 knockout
(p35-/-) mice, the cells of which are capable of
secreting p40, or p40 knockout (p40-/-) mice. Compared
with IL-12 wild-type controls, splenocytes obtained from both
p35-/- and p40-/- mice produced markedly
less IFN- after in vitro stimulation with Con A or alloantigens.
Interestingly, in vivo-sensitized Th1 were detected in both
p35-/- and p40-/- cardiac allograft
recipients. However, in vivo Th1 development was enhanced in
p35-/- recipients compared with p40-/-
animals, suggesting that endogenous p40 produced in
p35-/- mice may stimulate alloreactive Th1. Indeed,
neutralizing endogenous p40 with anti-IL-12 p40 mAb reduced Th1
development in p35-/- allograft recipients to that seen
in p40-/- mice. To determine whether Th1 development that
occurred in the absence of IL-12p70 and p40 required IFN-,
p40-/- allograft recipients were treated with
anti-IFN- mAb. Neutralizing IFN- did not inhibit in vivo Th1
development in p40-/- recipients and resulted in a unique
pathology of rejection characterized by vascular thromboses.
Collectively, these data suggest that 1) endogenous p40 may substitute
for IL-12p70 in alloantigen-specific Th1 sensitization in vivo and 2)
in vivo alloreactive Th1 development may occur independent of IL-12 and
IFN-, suggesting an alternate Th1-sensitizing pathway.
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