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Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
The adoptive transfer of TCR-transgenic T cells into syngeneic
recipients allows characterization of individual T cells during in vivo
immune responses. However, the proliferative behavior of individual T
cells and its relationship to effector and memory function has been
difficult to define. Here, we used a fluorescent dye to dissect and
quantify T cell proliferative dynamics in vivo. We find that the
average Ag-specific CD4+ T cell that undergoes division in
vivo generates >20 daughter cells. TCR and CD28 signals cooperatively
determine the degree of primary clonal expansion by increasing both the
proportion of Ag-specific T cells that divide and the number of rounds
of division the responding T cells undergo. Nonetheless, despite
optimal signaling, up to one-third of Ag-specific cells fail to divide
even though they show phenotypic evidence of Ag encounter.
Surprisingly, however, transgenic T cells maturing on a
RAG-2-/- background exhibit a responder frequency of
95–98% in vivo, suggesting that maximal proliferative potential
requires either a naive phenotype or allelic exclusion at the TCR
locus. Finally, studies reveal division cycle-dependent expression of
markers of T cell differentiation, such as CD44, CD45RB, and CD62L, and
show also that expression of the cytokines IFN-
and IL-2 depends
primarily on cell division rather than on receipt of costimulatory
signals. These results provide a quantitative assessment of T cell
proliferation in vivo and define the relationship between cell division
and other parameters of the immune response including cytokine
production, the availability of costimulation, and the capacity for
memory.
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Z.-m. Chen, M. J. O'Shaughnessy, I. Gramaglia, A. Panoskaltsis-Mortari, W. J. Murphy, S. Narula, M. G. Roncarolo, and B. R. Blazar IL-10 and TGF-{beta} induce alloreactive CD4+CD25- T cells to acquire regulatory cell function Blood, June 15, 2003; 101(12): 5076 - 5083. [Abstract] [Full Text] [PDF]
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A. G. Schrum and L. A. Turka The Proliferative Capacity of Individual Naive CD4+T Cells Is Amplified by Prolonged T Cell Antigen Receptor Triggering J. Exp. Med., September 16, 2002; 196(6): 793 - 803. [Abstract] [Full Text] [PDF]
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K. S. Schluns, K. Williams, A. Ma, X. X. Zheng, and L. Lefrancois Cutting Edge: Requirement for IL-15 in the Generation of Primary and Memory Antigen-Specific CD8 T Cells J. Immunol., May 15, 2002; 168(10): 4827 - 4831. [Abstract] [Full Text] [PDF]
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C. Arpin, G. Angelov, T. Walzer, M. Tomkowiak, and J. Marvel Hyperproliferative Response of a Monoclonal Memory CD8 T Cell Population Is Characterized by an Increased Frequency of Clonogenic Precursors J. Immunol., March 1, 2002; 168(5): 2147 - 2153. [Abstract] [Full Text] [PDF]
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K. E. Foulds, L. A. Zenewicz, D. J. Shedlock, J. Jiang, A. E. Troy, and H. Shen Cutting Edge: CD4 and CD8 T Cells Are Intrinsically Different in Their Proliferative Responses J. Immunol., February 15, 2002; 168(4): 1528 - 1532. [Abstract] [Full Text] [PDF]
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