INHIBITION OF PROLIFERATION AND DIFFERENTIATION DURING EARLY T-CELL DEVELOPMENT BY ANTITRANSFERRIN RECEPTOR ANTIBODY

Proliferating cells require iron and, therefore, express the transferr in receptor (CD71) that mediates cellular iron uptake. Cycling thymocy tes, which have the CD4(-)8(-)3(-), CD4(-)8(+)3(-), or CD4(+)8(+)3(-) phenotypes, also express CD71. The importance of CD71-mediated iron up take for proliferation and maturation of thymocytes was studied using fetal thymus organ cultures at day 14 of gestation and treating them f or 7 days with a CD71 monoclonal antibody (mAb). The intracellular iro n deficiency caused by this treatment, inhibits both proliferation and maturation of the thymocytes. Cell recovery was reduced by 60 %, but cells still expanded tenfold during the culture. Remarkably, the final maturation of alpha beta T cells was completely blocked as no thymocy tes with low or high CD3/alpha beta TcR expression developed. Moreover , only few cells reached the CD4(+)8(+)3(-) stage of T cell developmen t. CD4(-)8(-)3(-) thymocytes, however, as well as its CD44(-)25(+) sub set developed in normal numbers, suggesting that CD44(-)25(+) CD4(-)8( -)3(-) cells, or their immediate progeny, were most vulnerable to CD71 mAb treatment. The development of gamma delta T cells, which also exp ress CD71, was not affected in these cultures. This suggests that gamm a delta T cells are either less iron-dependent or possess alternative iron-uptake mechanisms. Thus, our observations indicate that CD71 trea tment, causing decreased intracellular iron levers, severely inhibits the major proliferation phase from the CD44(-)25(+) CD4(-)8(-)3(-) to the CD4(+)8(+)3(-) cells, and completely abrogates the final maturatio n of CD4(+)8(+)3(-) cells into alpha beta TcR-expressing cells. In con trast, proliferation and differentiation of the earliest thymic precur sors into CD44(-)25(+) CD4(-)8(-)3(-) cells is not affected by CD71 tr eatment.