Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: roles of IL-2 versus IL-15.
Regulatory T cell deficiency is evident in patients with lupus, but the casual [corrected] relationship and underlying mechanism leading to Treg deficiency are unclear. We analyzed the Treg profile, induction and functions of Treg in a lupus mouse model. A characteristic age-dependent biphasic change of Treg frequency was observed in the MRL/lpr mice, which developed a spontaneous lupus-like disease. After an early increase, Treg frequency in the peripheral lymphoid organs rapidly declined with age. Functionally, Treg from both young and old MRL/lpr mice were fully competent in suppressing the wild-type MRL/+ T effector cell (Teff) responses. Adoptive transfer of MRL/+ Treg markedly suppressed clinical disease in the MRL/lpr mice. We demonstrated that the reduced Treg frequency was a result of insufficient peripheral Treg expansion due to defective MRL/lpr Teff in IL-2 production, and the associated defects in dendritic cells, which could be fully restored by exogenous IL-2. In the absence of IL-2, MRL/lpr Teff but not MRL/lpr Treg were highly responsive to IL-15 and could expand rapidly due to enhanced IL-15R expression and IL-15 synthesis. These findings thus provide a clear causal relationship and immunological mechanism underlying Treg deficiency and systemic autoimmunity.
Yang
Cui-Hong
CH
Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Tian
Lina
L
Ling
Guang-Sheng
GS
Trendell-Smith
Nigel J
NJ
Ma
Liang
L
Lo
Chi-Kin
CK
Stott
David I
DI
Liew
Foo Y
FY
Huang
Fang-Ping
FP
D019264:Adoptive Transfer; D000367:Age Factors; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism* / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D011507:Proteinuria / Q000652:urine; D053647:Receptors, Interleukin-15 / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2; D053647:Receptors, Interleukin-15; D007371:Interferon-gamma