Progressive differentiation and commitment of CD8+ T cells to a poorly cytolytic CD8low phenotype in the presence of IL-4.
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 CD8low phenotype. This state was reversible in early differentiation. When single CD8low cells from 4-day cultures were cultured without IL-4, 65% gave rise to clones that partly or wholly comprised CD8high 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 CD8low 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.
Kienzle
Norbert
N
Cooperative Research Centre for Vaccine Technology and Queensland Institute of Medical Research, Brisbane, Queensland, Australia. norbertK@qimr.edu.au
Olver
Stuart
S
Buttigieg
Kathy
K
Groves
Penny
P
Janas
Michelle L
ML
Baz
Adriana
A
Kelso
Anne
A
D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013997:Time Factors
D016827:CD8 Antigens; D015847:Interleukin-4