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Progressive Differentiation and Commitment of CD8⁺ T Cells to a Poorly Cytolytic CD8^low Phenotype in the Presence of IL-4¹

Cooperative Research Centre for Vaccine Technology and Queensland Institute of Medical Research, Brisbane, Queensland, Australia

Exposure to IL-4 during activation of naive murine CD8⁺ T cells leads to generation of IL-4-producing effector cells with reduced surface CD8, low perforin, granzyme B and granzyme C mRNA, and poor cytolytic function. We show in this study that maximal development of these cells depended on exposure to IL-4 for the first 5 days of activation. Although IL-4 was not required at later times, CD8 T cell clones continued to lose surface CD8 expression with prolonged culture, suggesting commitment to the CD8^low phenotype. This state was reversible in early differentiation. When single CD8^low cells from 4-day cultures were cultured without IL-4, 65% gave rise to clones that partly or wholly comprised CD8^high cells; the proportion of reverted clones was reduced or increased when the cells were cloned in the presence of IL-4 or anti-IL-4 Ab, respectively. CD8 expression positively correlated with perforin and granzyme A, B, and C mRNA, and negatively correlated with IL-4 mRNA levels among these clones. By contrast, most CD8^low cells isolated at later time points maintained their phenotype, produced IL-4, and exhibited poor cytolytic function after many weeks in the absence of exogenous IL-4. We conclude that IL-4-dependent down-regulation of CD8 is associated with progressive differentiation and commitment to yield IL-4-producing cells with little cytolytic activity. These data suggest that the CD4^–CD8^– cells identified in some disease states may be the product of a previously unrecognized pathway of effector differentiation from conventional CD8⁺ T cells.

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