Effect of anti-CD4 on CD4 subsets. I. Anti-CD4 preferentially deletes resting, naive CD4 cells and spares activated CD4 cells.
Anti-CD4 has been extensively studied in murine models of autoimmunity and transplantation. The timing of anti-CD4 administration in these systems is critical because anti-CD4 effectively blocks primary T-dependent responses but does not diminish ongoing or memory responses in immunized animals. These differential effects suggest that anti-CD4 suppresses a subpopulation of CD4+ cells. We previously observed in vitro that simultaneous activation through TCR-T3 rescued CD4+ cells from anti-CD4 elimination. From this we hypothesized that activated CD4+ cells resisted the effects of anti-CD4. We now show that in vivo treatment with anti-CD4 preferentially eliminated resting, naive CD4+ cells rather than memory and effector CD4+ cells. The CD4+ cells that remained after anti-CD4 treatment exhibited evidence of recent activation, because a higher percentage expressed IL-2R, regardless of subset phenotype. Moreover, Mls-1-primed, anti-CD4-treated mice showed a higher percentage of V beta 6+ (Mls-1 reactive) CD4+ cells than either unprimed mice, anti-CD4-treated mice, or Mls-1-primed controls, implicating the importance of recent activation. These anti-CD4-resistant cells also retained their functional abilities. T cells from BALB/c mice treated with anti-CD4 after Mls-1 immunization maintained their MLR proliferation against DBA/2 stimulator cells. In addition, anti-CD4 did not reduce T-dependent antibody responses in mice previously primed against the Ag cholera toxin or SRBC. Thus, activated CD4+ cells resist the suppressive effects of anti-CD4. Our findings have critical implications for the ongoing clinical trials using anti-CD4.
Chace
J H
JH
Department of Medicine, University of Iowa College of Medicine, Iowa City 52242.
Cowdery
J S
JS
Field
E H
EH
D000818:Animals; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016747:Minor Lymphocyte Stimulatory Antigens / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D016747:Minor Lymphocyte Stimulatory Antigens