Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes.
The lineage relationship between short-lived effector T cells and long-lived memory cells is not fully understood. We have described T-GFP mice previously, in which naive and early activated T cells express GFP uniformly, whereas cells that have differentiated into effector cytotoxic T cells selectively lose GFP expression. Here we studied antigen-specific CD8 T cell differentiation using T-GFP mice crossed to the TCR transgenic (Tg) mice P14 (specific for the lymphocytic choriomeningitis virus glycoprotein peptide, gp33-41). After activation with antigenic peptide, P14XT-GFP CD8(+) T cells cultured in high-dose IL-2 developed into cells with effector phenotype and function: they were blastoid, lost GFP expression, expressed high levels of activation and effector markers, and were capable of immediate cytotoxic function. In contrast, cells cultured in IL-15 or low-dose IL-2 never developed into full-fledged effector cells. Rather, they resembled memory cells: they were smaller, were GFP(+), did not express effector markers, and were incapable of immediate cytotoxicity. However, they mediated rapid-recall responses in vitro. After adoptive transfer, they survived in vivo for at least 10 weeks and mounted a secondary immune response after antigen rechallenge that was as potent as endogenously generated memory cells. In addition to providing a simple means to generate memory cells in virtually unlimited numbers, our results suggest that effector differentiation is not a prerequisite for memory cell generation.
Manjunath
N
N
The Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. swamy@cbr.med.harvard.edu
Shankar
P
P
Wan
J
J
Weninger
W
W
Crowley
M A
MA
Hieshima
K
K
Springer
T A
TA
Fan
X
X
Shen
H
H
Lieberman
J
J
von Andrian
U H
UH
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D006023:Glycoproteins / Q000276:immunology; D049452:Green Fluorescent Proteins; D007156:Immunologic Memory; D066298:In Vitro Techniques; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology
D000956:Antigens, Viral; D006023:Glycoproteins; D019409:Interleukin-15; D007376:Interleukin-2; D008164:Luminescent Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; D049452:Green Fluorescent Proteins