H. Gudmundsdottir et al., Dynamics and requirements of T cell clonal expansion in vivo at the single-cell level: Effector function is linked to proliferative capacity, J IMMUNOL, 162(9), 1999, pp. 5212-5223
The adoptive transfer of TCR-transgenic T cells into syngeneic recipients a
llows characterization of individual T cells during in vivo immune response
s. However, the proliferative behavior of individual T cells and its relati
onship to effector and memory function has been difficult to define, Here,
we used a fluorescent dye to dissect and quantify T cell proliferative dyna
mics in vivo, We find that the average Ag-specific CD4(+) T cell that under
goes division in vivo generates >20 daughter cells. TCR and CD28 signals co
operatively determine the degree of primary clonal expansion by increasing
both the proportion of Ag-specific T cells that di ride and the number of r
ounds of division the responding T cells undergo. Nonetheless, despite opti
mal signaling, up to one-third of Ag-specific cells fail to divide even tho
ugh they show phenotypic evidence of Ag encounter. Surprisingly, however! t
ransgenic T cells maturing on a RAG-2(-/-) background exhibit a responder f
requency of 95-98% in vivo! suggesting that maximal proliferative potential
requires either a naive phenotype or allelic exclusion at the TCR alpha lo
cus. Finally, studies reveal division cycle-dependent expression of markers
of T cell differentiation, such as CD44, CD45RB, and CD62L and show also t
hat expression of the cytokines IFN-gamma and IL-2 depends primarily on cel
l division rather than on receipt of costimulatory signals, These results p
rovide 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.