CD8α-Deficient Mice Are Highly Susceptible to 5-Fluorouracil-Induced Lethality

Intestinal intraepithelial lymphocytes (i-IEL) expressing CD8α are located in the intestine and may confer protection against invasion of intestinal microflora. We found that mice rendered deficient in CD8α molecules by homologous recombination were susceptible to 5-fluorouracil (5-FU)-induced lethality accompanied by translocation of members of the enterobacteria. The number of i-IEL was greatly reduced on day 6 after 5-FU administration in both CD8α(+/−) mice and CD8α(−/−) mice, whereas the recovery of the level of i-IEL thereafter was significantly impaired in CD8α(−/−) mice compared with that in CD8α(+/−) mice. The ability of i-IEL to produce gamma interferon in response to immobilized T-cell receptor (TCR) αβ or TCR γδ monoclonal antibodies was significantly lower in CD8α(−/−) mice than in CD8α(+/−) mice. Transfer of CD8(+) i-IEL conferred significant protection against 5-FU-induced lethality in CD8α(−/−) mice. The results suggest that CD8(+) i-IEL play an important role in protection against 5-FU-induced lethality with translocation of Enterobacteriaceae.