Immunomodulatory properties of a viral homolog of human interleukin-10 expressed by human cytomegalovirus during the latent phase of infection.
Human cytomegalovirus (HCMV) establishes a latent infection in hematopoietic cells, from which it can reactivate to cause significant disease in immunocompromised individuals. HCMV expresses a functional homolog of the immunosuppressive cytokine interleukin-10 (termed cmvIL-10), and alternate splicing of the cmvIL-10 transcript results in expression of a latency-associated cmvIL-10 transcript (LAcmvIL-10). To determine whether LAcmvIL-10 encodes immunosuppressive functions, recombinant LAcmvIL-10 protein was generated, and its impact on major histocompatibility complex class II (MHC-II) expression was examined on granulocyte macrophage progenitor cells (GM-Ps) and monocytes. LAcmvIL-10 (and cmvIL-10) downregulated MHC-II on the surfaces of both cell types. This downregulation was associated with a decrease in total MHC-II protein and transcription of components of the MHC-II biosynthesis pathway. Unlike cmvIL-10, LAcmvIL-10 did not trigger phosphorylation of Stat3, and its ability to downregulate MHC-II was not blocked by neutralizing antibodies to the human IL-10 receptor, suggesting that LAcmvIL-10 either does not engage the cellular IL-10 receptor or utilizes it in a different manner from cmvIL-10. The impact of LAcmvIL-10 on dendritic cell (DC) maturation was also assessed. In contrast to cmvIL-10, LAcmvIL-10 did not inhibit the expression of costimulatory molecules CD40, CD80, and CD86 and the maturation marker CD83 on DCs, nor did it inhibit proinflammatory cytokines (IL-1alpha, IL-1beta, IL-6 and tumor necrosis factor alpha). Thus, LAcmvIL-10 retains some, but not all, of the immunosuppressive functions of cmvIL-10. As GM-Ps and monocytes support latent infection, expression of LAcmvIL-10 may enable HCMV to avoid immune recognition and clearance during latency.
Jenkins
C
C
Centre for Virus Research, Westmead Millennium Institute, P.O. Box 412, Westmead, NSW 2145, Australia. barry_slobedman@wmi.usyd.edu.au.
Garcia
W
W
Godwin
M J
MJ
Spencer
J V
JV
Stern
J Lewis
JL
Abendroth
A
A
Slobedman
B
B
D015703:Antigens, CD / Q000032:analysis; D000954:Antigens, Surface / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis; D003587:Cytomegalovirus / Q000276:immunology* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology*; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology; D015536:Down-Regulation; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance; D009000:Monocytes / Q000737:chemistry / Q000276:immunology; D023461:Myeloid Progenitor Cells / Q000737:chemistry / Q000276:immunology; D010766:Phosphorylation; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology*; D017735:Virus Latency
D015703:Antigens, CD; D000954:Antigens, Surface; C446339:CMV IL-10 protein, Cytomegalovirus; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014764:Viral Proteins