Regulatory CD8+ T Cells Control Neonatal Tolerance to a Th2-Mediated Autoimmunity

Abstract

Exposure of newborn animals to a foreign Ag may result in immunological tolerance to that specific Ag, a phenomenon called neonatal tolerance. We have previously reported that neonatal administration to Brown-Norway rats of mercury, a heavy metal toxicant, induces a dominant tolerance, specific for the chemical otherwise responsible for Th2 cell-mediated autoimmune responses in this susceptible strain of rats. Neonatal exposure to Ags can prime immunity, rather than inactivate or delete responses, and sustain regulatory functions effective against autoreactive T cells. Here, we address whether such a tolerant response is due to the generation of regulatory cells. The results suggest that the CD8+ T cell subset is involved in neonatal tolerance to mercuric salt-induced Th2 autoimmune disease. Thus, we demonstrate that in vivo CD8 depletion breaks tolerance following mercury recall in animals under a neonatal tolerance protocol. Furthermore, adoptive cotransfer of splenocytes from naive and tolerant rats as well as transfer of CD8+ T cells from tolerant animals prevent naive syngeneic rats from developing pathologic Th2 immune responses. These observations indicate that CD8+ T cells are endowed with regulatory functions in neonatal tolerance and mediate active suppression. Moreover, neonatal tolerance induced the expansion of CD8+CD45RChigh T cells and the emergence of a high percentage of IFN-γ-synthesizing CD8+ T cells, which probably reflects the implication of regulatory Tc1 cells. Thus, in vivo induction of neonatal tolerance suppresses Th2 autoimmune responses via generation of a CD8+ cell-mediated regulatory response.

Regulation of Th2 Responses and Allergic Inflammation through Bystander Activation of CD8+ T Lymphocytes in Early Life

“…Considering the neonates, we and other investigators reported that regulatory CD8 + T cells controlling Th2 pathology are effective (20,21). In both cases, the induction of IFN-g-producing CD8…”

Anti-TCR Antibody Treatment Activates a Novel Population of Nonintestinal CD8αα+TCRαβ+ Regulatory T Cells and Prevents Experimental Autoimmune Encephalomyelitis

“…These cells are efficient in suppressing the priming or expansion of T cell immunity (11,12). In addition, there is ample evidence for the existence of regulatory CD8 T cells (CD8 Tregs) that play a role in autoimmune diseases, tumor control, infection, transplantation tolerance, neonatal tolerance, and oral tolerance (13)(14)(15)(16)(17)(18)(19). However, characteristic surface markers for identifying these CD8 Tregs and the molecular mechanisms by which they induce regulation have yet to be thoroughly characterized.…”

“…Total mRNA was extracted from cells using the RNeasy mini kit (Qiagen) and subjected to cDNA synthesis with an oligo d(T) [12][13][14][15][16][17][18] Real-time PCR was performed using the Brilliant SYBR Green quantitative PCR kit (Stratagene) on a Stratagene Mx3000p machine. The calculation of comparative mRNA expression was performed by the Stratagene software and was designated as relative quantity after normalization against internal control genes (L32 and cyclophilin) and after consideration of the amplification efficiency of individual genes.…”

Immunological effects of mercury (IUPAC Technical Report)

“…When mercury-sensitive newborns are treated with mercury(II) chloride, they become mercury-resistant [51]. This might be caused by a CD8-T-cell-mediated reaction [52].…”