Anti-HIV-1 and chemotactic activities of human stromal cell-derived factor 1alpha (SDF-1alpha) and SDF-1beta are abolished by CD26/dipeptidyl peptidase IV-mediated cleavage.
CD26 is a leukocyte-activation antigen that is expressed on T lymphocytes and macrophages and possesses dipeptidyl peptidase IV (DPPIV) activity, whose natural substrates have not been identified yet. CXC chemokines, stromal cell-derived factor 1alpha (SDF-1alpha) and 1beta (SDF-1beta), sharing the receptor CXCR-4, are highly efficacious chemoattractants for resting lymphocytes and CD34(+) progenitor cells, and they efficiently block the CXCR-4-mediated entry into cells of T cell line tropic strains of HIV type 1 (HIV-1). Here we show that both the chemotactic and antiviral activities of these chemokines are abrogated by DPPIV-mediated specific removal of the N-terminal dipeptide, not only when the chemokines are produced in transformed mouse L cell line to express human CD26 but also when they were exposed to a human T cell line (H9) physiologically expressing CD26. Mutagenesis of SDF-1alpha confirmed the critical requirement of the N-terminal dipeptide for its chemotactic and antiviral activities. These data suggest that CD26-mediated cleavage of SDF-1alpha and SDF-1beta likely occurs in human bodies and promotes HIV-1 replication and disease progression. They may also explain why memory function of CD4(+) cells is preferentially lost in HIV-1 infection. Furthermore, CD26 would modulate various other biological processes in which SDF-1alpha and SDF-1beta are involved.
Shioda
T
T
Department of Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan. shioda@ims.u-tokyo.ac.jp
Kato
H
H
Ohnishi
Y
Y
Tashiro
K
K
Ikegawa
M
M
Nakayama
E E
EE
Hu
H
H
Kato
A
A
Sakai
Y
Y
Liu
H
H
Honjo
T
T
Nomoto
A
A
Iwamoto
A
A
Morimoto
C
C
Nagai
Y
Y
D000818:Animals; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000276:immunology* / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D051379:Mice; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D018819:Dipeptidyl Peptidase 4