Four functionally distinct populations of human effector-memory CD8+ T lymphocytes.
In humans, the pathways of memory and effector T cell differentiation remain poorly defined. We have dissected the functional properties of ex vivo effector-memory (EM) CD45RA-CCR7- T lymphocytes present within the circulating CD8+ T cell pool of healthy individuals. Our studies show that EM T cells are heterogeneous and are subdivided based on differential CD27 and CD28 expression into four subsets. EM(1) (CD27+CD28+) and EM(4) (CD27-CD28+) T cells express low levels of effector mediators such as granzyme B and perforin and high levels of CD127/IL-7Ralpha. EM(1) cells also have a relatively short replicative history and display strong ex vivo telomerase activity. Therefore, these cells are closely related to central-memory (CD45RA-CCR7+) cells. In contrast, EM(2) (CD27+CD28-) and EM(3) (CD27-CD28-) cells express mediators characteristic of effector cells, whereby EM(3) cells display stronger ex vivo cytolytic activity and have experienced larger numbers of cell divisions, thus resembling differentiated effector (CD45RA+CCR7-) cells. These data indicate that progressive up-regulation of cytolytic activity and stepwise loss of CCR7, CD28, and CD27 both characterize CD8+ T cell differentiation. Finally, memory CD8+ T cells not only include central-memory cells but also EM(1) cells, which differ in CCR7 expression and may therefore confer memory functions in lymphoid and peripheral tissues, respectively.
Romero
Pedro
P
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research-Lausanne Branch, University Hospital of Lausanne, Lausanne, Switzerland.
Zippelius
Alfred
A
Kurth
Isabel
I
Pittet
Mikaël J
MJ
Touvrey
Cédric
C
Iancu
Emanuela M
EM
Corthesy
Patricia
P
Devevre
Estelle
E
Speiser
Daniel E
DE
Rufer
Nathalie
N
D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000145:classification* / Q000276:immunology*; D002454:Cell Differentiation; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D053804:Granzymes / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory; D053699:Interleukin-7 Receptor alpha Subunit / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000032:analysis / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000145:classification* / Q000276:immunology*; D016615:Telomere / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics
C498126:CCR6 protein, mouse; D018106:CD28 Antigens; D053699:Interleukin-7 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D020395:Receptors, Interleukin-7; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C415350:interleukin-7 receptor, alpha chain; D054353:Perforin; D053804:Granzymes