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*
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Basel Institute for Immunology, Basel, Switzerland; and
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Alloreactive T cell precursor frequency was measured in vivo using
fluorescent dye labeling in combination with novel models based on
lymphocyte activation and recovery. CFSE-labeled C57BL/6
(H-2b) spleen and lymph node cells were adoptively
transferred to C57BL/6xDBA F1 (H-2b/d)
recipients, a parent
F1 MHC mismatch in which only donor
cells respond. Recipients were sacrificed at serial time points to
assess engraftment efficiency, and the extent of donor cell activation
and proliferation. These data were used to calculate alloreactive T
cell frequencies that varied 30-fold (0.71 ± 0.31% to 21.05
± 3.62%), depending upon whether it was assumed that all donor cells
injected became established and were capable of responding, or that
only those present at later time points (24–72 h) were available to
respond. By measuring the number of cells established in the recipient
24 h after transfer, before proliferation, we calculated an in
vivo alloreactive frequency of 
7%. Using CD69 expression at 48
h to quantify activation, we found that 40–50% of the alloactivated
CD4+ donor T cells do not divide. Studies of cotransferred
congenic and allogeneic cells demonstrated that bystander proliferation
does not occur. We conclude that accurate calculations of alloreactive
precursor frequency must account for both proliferation and cell
engraftment. When this is done, a high percentage of alloreactive T
cells exists across an MHC mismatch, but not all alloreactive cells
proliferate in vivo. Bystander proliferation is negligible, revealing
exquisite specificity to the alloresponse. These data provide a novel
approach to quantify alloreactive T cell responses during specific
immunomodulatory strategies in vivo.
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