Peripheral human CD8+CD28+ T lymphocytes give rise to CD28- progeny, but IL-4 prevents loss of CD28 expression

Abstract

At birth, virtually all peripheral CD8+ T cells express the CD28 co-stimulatory molecule, but healthy human adults accumulate CD28-CD8+ T cells that often express the CD57 marker. While these CD28- subpopulations are known to exert effector-type functions, the generation, maintenance and regulation of CD28- (CD57+ or CD57-) subpopulations remain unresolved. Here, we compared the differentiation of CD8+CD28(bright)CD57- T cells purified from healthy adults or neonates and propagated in IL-2, alone or with IL-4. With IL-2 alone, CD8+CD28(bright)CD57- T cell cultures yielded a prevailing CD28- subpopulation. The few persisting CD28(dim) and the major CD28- cells were characterized by similar telomere shortening at the plateau phase of cell growth. Cultures from adults donors generated four final CD8+ phenotypes: a major CD28-CD57+, and three minor CD28-CD57-, CD28(dim)CD57- and CD28(dim)CD57(dim). These four end-stage CD8+ subpopulations displayed a fairly similar representation of TCR V(β) genes. In cultures initiated with umbilical cord blood, virtually all the original CD8+CD28(bright) T cells lost expression of CD28, but none acquired CD57 with IL-2 alone. IL-4 impacted on the differentiation pathways of the CD8+CD28(bright)CD57- T cells: the addition of IL-4 led both the neonatal and the adult lymphocytes to keep their expression of CD28. Thus, CD8+CD28(bright)CD57- T cells can give rise to four end-stage subpopulations, the balance of which is controlled by both the cytokine environment, IL-4 in particular, and the proportions of naive and memory CD8+CD28+ T cells.