TIM-3: a novel regulatory molecule of alloimmune activation.
T cell Ig domain and mucin domain (TIM)-3 has previously been established as a central regulator of Th1 responses and immune tolerance. In this study, we examined its functions in allograft rejection in a murine model of vascularized cardiac transplantation. TIM-3 was constitutively expressed on dendritic cells and natural regulatory T cells (Tregs) but only detected on CD4(+)FoxP3(-) and CD8(+) T cells in acutely rejecting graft recipients. A blocking anti-TIM-3 mAb accelerated allograft rejection only in the presence of host CD4(+) T cells. Accelerated rejection was accompanied by increased frequencies of alloreactive IFN-γ-, IL-6-, and IL-17-producing splenocytes, enhanced CD8(+) cytotoxicity against alloantigen, increased alloantibody production, and a decline in peripheral and intragraft Treg/effector T cell ratio. Enhanced IL-6 production by CD4(+) T cells after TIM-3 blockade plays a central role in acceleration of rejection. Using an established alloreactivity TCR transgenic model, blockade of TIM-3 increased allospecific effector T cells, enhanced Th1 and Th17 polarization, and resulted in a decreased frequency of overall number of allospecific Tregs. The latter is due to inhibition in induction of adaptive Tregs rather than prevention of expansion of allospecific natural Tregs. In vitro, targeting TIM-3 did not inhibit nTreg-mediated suppression of Th1 alloreactive cells but increased IL-17 production by effector T cells. In summary, TIM-3 is a key regulatory molecule of alloimmunity through its ability to broadly modulate CD4(+) T cell differentiation, thus recalibrating the effector and regulatory arms of the alloimmune response.
Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Boston, MA 02115, USA.
Olaf
O
Boenisch
Francesca
F
D'Addio
Toshihiko
T
Watanabe
Wassim
W
Elyaman
Ciara N
CN
Magee
Melissa Y
MY
Yeung
Robert F
RF
Padera
Scott J
SJ
Rodig
Takaya
T
Murayama
Katsunori
K
Tanaka
Xueli
X
Yuan
Takuya
T
Ueno
Anke
A
Jurisch
Bechara
B
Mfarrej
Hisaya
H
Akiba
Hideo
H
Yagita
Nader
N
Najafian
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism; D016027:Heart Transplantation / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011991:Receptors, Virus / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D014184:Transplantation, Homologous
D016207:Cytokines; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; D011991:Receptors, Virus