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J. Exp. Med.,
Volume 188, Number 11, December 7, 1998 2007-2017
-mediated Splenic Anergy
By
From the Department of Microbiology, University of Tennessee, Knoxville, Tennessee 37996
Induction of neonatal T cell tolerance to soluble antigens requires the use of incomplete
Freund's adjuvant (IFA). The side effects that could be associated with IFA and the ill-defined mechanism underlying neonatal tolerance are setbacks for this otherwise attractive strategy for
prevention of T cell-mediated autoimmune diseases. Presumably, IFA contributes a slow antigen release and induction of cytokines influential in T cell differentiation. Immunoglobulins
(Igs) have long half-lives and could induce cytokine secretion by binding to Fc receptors on
target cells. Our hypothesis was that peptide delivery by Igs may circumvent the use of IFA and
induce neonatal tolerance that could confer resistance to autoimmunity. To address this issue
we used the proteolipid protein (PLP) sequence 139-151 (hereafter referred to as PLP1),
which is encephalitogenic and induces experimental autoimmune encephalomyelitis (EAE) in
SJL/J mice. PLP1 was expressed on an Ig, and the resulting Ig-PLP1 chimera when injected in
saline into newborn mice confers resistance to EAE induction later in life. Mice injected with Ig-PLP1 at birth and challenged as adults with PLP1 developed T cell proliferation in the
lymph node but not in the spleen, whereas control mice injected with Ig-W, the parental Ig
not including PLP1, developed T cell responses in both lymphoid organs. The lymph node T
cells from Ig-PLP1 recipient mice were deviated and produced interleukin (IL)-4 instead of
IL-2, whereas the spleen cells, although nonproliferative, produced IL-2 but not interferon (IFN)-
. Exogenous IFN-, as well as IL-12, restored splenic proliferation in an antigen specific manner. IL-12-rescued T cells continued to secrete IL-2 and regained the ability to produce IFN-. In vivo, administration of anti-IL-4 antibody or IL-12 restored disease severity.
Therefore, adjuvant-free induced neonatal tolerance prevents autoimmunity by an organ-specific regulation of T cells that involves both immune deviation and a new form of cytokine- dependent T cell anergy.
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