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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3851-3859
IMMUNOBIOLOGY
Generation and biochemical analysis of human effector CD4 T
cells: alterations in tyrosine phosphorylation and loss of CD3
expression
Sandeep Krishnan,
Vishal G. Warke,
Madhusoodana P. Nambiar,
Henry K. Wong,
George C. Tsokos, and
Donna L. Farber
From the Department of Surgery, University of Maryland,
Baltimore; Department of Cellular Injury, Walter Reed Army Institute of
Research (WRAIR), Silver Spring, MD; and Department of Medicine,
Uniformed Services University of the Health Sciences, Bethesda, MD.
Human effector T cells have been difficult to isolate and
characterize due to their phenotypic and functional similarity to the
memory subset. In this study, a biochemical approach was used to
analyze human effector CD4 T cells generated in vitro by activation with anti-CD3 and autologous monocytes for 3 to 5 days. The resultant effector cells expressed the appropriate activation/differentiation markers and secreted high levels of interferon  (IFN-) when restimulated. Biochemically, effector CD4 T cells exhibited increases in total intracellular tyrosine phosphorylation and effector-associated phosphorylated species. Paradoxically, these alterations in tyrosine phosphorylation were concomitant with greatly reduced expression of
CD3 and CD3 signaling subunits coincident with a reduction in
surface T-cell receptor (TCR) expression. Because loss of CD3 has
also been detected in T cells isolated ex vivo from individuals with
cancer, chronic viral infection, and autoimmune diseases, the
requirements and kinetics of CD3 down-regulation were examined. The
loss of CD3 expression persisted throughout the course of effector
T-cell differentiation, was reversible on removal from the activating
stimulus, and was modulated by activation conditions. These biochemical
changes occurred in effector T cells generated from naive or memory CD4
T-cell precursors and distinguished effector from memory T cells. The
results suggest that human effector T-cell differentiation is
accompanied by alterations in the TCR signal transduction and that loss
of CD3 expression may be a feature of chronic T-cell activation and
effector generation in vivo.
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