The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/1/141/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 1, January 6, 1997 141-152

Articles

Downregulation of CD1 Marks Acquisition of Functional Maturation of Human Thymocytes and Defines a Control Point in Late Stages of Human T Cell Development

Pieter Res*, Bianca Blom*, Toshiyuki Hori{ddagger}, Kees Weijer*, and Hergen Spits*

From the * Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands; and {ddagger} Laboratory of AIDS Immunology, Institute for Virus Research, Kyoto University, Kyoto, Japan

We have investigated whether in the human thymus transition of CD4+CD8+ double positive (DP) to CD4+ or CD8+ single positive (SP) cells is sufficient for generation of functional immunocompetent T cells. Using the capacity of thymocytes to expand in vitro in response to PHA and IL-2 as a criterion for functional maturity, we found that functional maturity of both SP and DP thymocytes correlates with downregulation of CD1a. CD1a– cells with a persistent DP phenotype were also found in neonatal cord blood, suggesting that at least a proportion of mature DP cells can emigrate from the thymus. The requirements for generating functional T cells were investigated in a hybrid human/mouse fetal thymic organ culture. MHC class II– positive, but not MHC class II–negative, mouse thymic microenvironments support differentiation of human progenitors into TCR{alpha}β+CD4+ SP cells, indicating that mouse MHC class II can positively select TCR{alpha}β+CD4+ SP human cells. Strikingly, these SP are arrested in the CD1a+ stage and could not be expanded in vitro with PHA and IL-2. CD1a+CD4+ SP thymocytes do not represent an end stage population because purified CD1a+CD4+ SP thymocytes differentiate to expandable CD1a– cells upon cocultivation with human thymic stromal cells. Taken together these data indicate that when CD1a+ DP TCR{alpha}βlow cells mature, these cells interact with MHC, but that an additional, apparently species-specific, signal is required for downregulation of CD1a to generate functional mature TCR{alpha}β+ cells.

Address correspondence to Hergen Spits, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

This work was supported by a grant from the Dutch Cancer Foundation (No. NKI 95-960).

1Abbreviations used in this paper: DP, double positive; FTOC, fetal thymic organ culture; HPRT, hypoxanthine phosphoribosyl transferase; RAG, recombination activating gene; SP, single positive; TRC, TriColor.


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