Disruption of TNF-α/TNFR1 function in resident skin cells impairs host immune response against cutaneous vaccinia virus infection.
One strategy adopted by vaccinia virus (VV) to evade the host immune system is to encode homologs of TNF receptors (TNFRs) that block TNF-α function. The response to VV skin infection under conditions of TNF-α deficiency, however, has not been reported. We found that TNFR1-/- mice developed larger primary lesions, numerous satellite lesions, and higher skin virus levels after VV scarification. Following their recovery, VV-scarified TNFR1-/- mice were fully protected against challenge with a lethal intranasal dose of VV, suggesting these mice had developed an effective memory immune response. A functional systemic immune response was further demonstrated by enhanced production of VV-specific IFN-γ and VV-specific CD8(+) T cells in spleens and draining lymph nodes. Interestingly, bone marrow (BM)-reconstitution studies using wild-type (WT) BM in TNFR1-/- host mice, but not TNFR1-/- BM in WT host mice, reproduced the original results seen in TNFR1-/- mice, indicating that TNFR1 deficiency in resident skin cells, rather than hematopoietic cells, accounts for the impaired cutaneous immune response. Our data suggest that lack of TNFR1 leads to a skin-specific immune deficiency, and that resident skin cells have a crucial role in mediating an optimal immune defense to VV cutaneous infection via TNF-α/TNFR1 signaling.
Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Tian
T
Tian
Krista
K
Dubin
Qiushuang
Q
Jin
Ali
A
Qureshi
Sandra L
SL
King
Luzheng
L
Liu
Xiaodong
X
Jiang
George F
GF
Murphy
Thomas S
TS
Kupper
Robert C
RC
Fuhlbrigge
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D018414:CD8-Positive T-Lymphocytes; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000276:immunology*; D012867:Skin / Q000276:immunology* / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014615:Vaccinia / Q000276:immunology* / Q000473:pathology; D014616:Vaccinia virus / Q000276:immunology*; D019562:Viral Load
D000914:Antibodies, Viral; D007074:Immunoglobulin G; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma