TY - JOUR
T1 - Lack of coreceptor allows survival of chronically stimulated double-negative α/β T cells
T2 - Implications for autoimmunity
AU - Hamad, Abdel Rahim A.
AU - Srikrishnan, Ananth
AU - Mirmonsef, Paria
AU - Broeren, Chris P.M.
AU - June, Carl H.
AU - Pardoll, Drew
AU - Schneck, Jonathan P.
PY - 2001/5/21
Y1 - 2001/5/21
N2 - Lymphoproliferative diseases are characterized by massive accumulation of CD4-CD8-B220+ (double-negative [DN]) T cells in peripheral organs. Although evidence indicates these cells are derived from mature autoreactive α/β T cells, the significance of coreceptor downregulation is not known. In this study, we examined the role CD4 coreceptor plays in the survival of repeatedly stimulated T cells. CD4+/+ and CD4-/- T cells from AND T cell receptor (TCR) transgenic mice exhibited similar phenotypes after antigenic stimulation, but the CD4-/- T cells survived in much larger numbers than the CD4+/+ cells upon primary and secondary major histocompatibility complex (MHC)/peptide stimulation. Enhanced survival of CD4-/- T cells was due to decreased apoptosis rather than enhanced proliferation. Similarly, circumvention of the CD4/MHC interaction by using a surrogate TCR ligand that does not engage CD4 led to significant enhancement of CD4+/+ cells than when stimulated with MHC/peptide. Finally, we generated DN B220+ T cells using an in vitro model system and showed they were more tolerant to chronic stimulation than CD4+/+ cells. Together, these results indicate that coreceptor engagement controls expansion of normal T cells. In the absence of coreceptor, T cells survive chronic stimulation and express B220 as seen in autoimmune lymphoproliferative diseases.
AB - Lymphoproliferative diseases are characterized by massive accumulation of CD4-CD8-B220+ (double-negative [DN]) T cells in peripheral organs. Although evidence indicates these cells are derived from mature autoreactive α/β T cells, the significance of coreceptor downregulation is not known. In this study, we examined the role CD4 coreceptor plays in the survival of repeatedly stimulated T cells. CD4+/+ and CD4-/- T cells from AND T cell receptor (TCR) transgenic mice exhibited similar phenotypes after antigenic stimulation, but the CD4-/- T cells survived in much larger numbers than the CD4+/+ cells upon primary and secondary major histocompatibility complex (MHC)/peptide stimulation. Enhanced survival of CD4-/- T cells was due to decreased apoptosis rather than enhanced proliferation. Similarly, circumvention of the CD4/MHC interaction by using a surrogate TCR ligand that does not engage CD4 led to significant enhancement of CD4+/+ cells than when stimulated with MHC/peptide. Finally, we generated DN B220+ T cells using an in vitro model system and showed they were more tolerant to chronic stimulation than CD4+/+ cells. Together, these results indicate that coreceptor engagement controls expansion of normal T cells. In the absence of coreceptor, T cells survive chronic stimulation and express B220 as seen in autoimmune lymphoproliferative diseases.
KW - Apoptosis
KW - B220
KW - CD4 coreceptor
KW - Double-negative T cell
KW - Lymphoproliferation
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U2 - 10.1084/jem.193.10.1113
DO - 10.1084/jem.193.10.1113
M3 - Article
C2 - 11369783
AN - SCOPUS:0035926955
SN - 0022-1007
VL - 193
SP - 1113
EP - 1121
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -