Combination of IL-10 and IL-2 induces oligoclonal human CD4 T cell expansion during xenogeneic and allogeneic GVHD in humanized mice
Sojan Abraham,
Hua Guo,
Jang-gi Choi,
Chunting Ye,
Midhun Ben Thomas,
Nora Ortega,
Alok Dwivedi,
N. Manjunath,
Guohua Yi,
Premlata Shankar
Affiliations
Sojan Abraham
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA; Department of Infectious Disease Research, Drug Development, Southern Research Institute, Frederick MD, USA; Corresponding authors.
Hua Guo
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
Jang-gi Choi
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA; KM Application Center, Korea Institute of Oriental Medicine, 70 Chemdan-ro, Dong-gu, Daegu 701-300, Republic of Korea
Chunting Ye
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA; The Jackson Laboratory-west, 1650 Santa Ana Avenue, Sacramento, CA, USA
Midhun Ben Thomas
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
Nora Ortega
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
Alok Dwivedi
Division of Biostatistics and Epidemiology, Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
N. Manjunath
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
Guohua Yi
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
Premlata Shankar
Department of Biomedical Sciences, Center of Emphasis in Infectious Disease, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA; Corresponding authors.
IL-10 is a crucial anti-inflammatory cytokine which can also exert a seemingly divergent immunostimulatory effects under certain conditions. We found high levels of the cytokine in a xenogeneic GVHD model where NOD-scid IL2rγcnull (NSG) mice were transplanted with human PBMCs in presence of IL-2. Presence of exogenous IL-10 altered the kinetics of IL-2 induced human T cell reconstitution in vivo, showing an initial delay, followed by rapid expansion. Further, compared to IL-2 alone, treatment with IL-2 in combination with IL-10 increased survival in most animals and completely protected ∼20% of mice from GVHD. Additionally, IL-2 induced expansion of both CD4+ and CD8+ xenoreactive T cells whereas a combination of IL-2 and IL-10 resulted in selective expansion of CD4+ T cells only. TCR Vβ repertoire analysis of CD4+ T cells showed that in contrast to IL-2 alone, simultaneous presence of both cytokines drastically reduced the Vβ repertoire of the expanded CD4+ T cells. Highly restricted Vβ usage was also observed when the cytokine combination was tested in an allogeneic GVHD model where NOD-scid IL2rγcnull mice expressing HLA-DR4 (NSG-DR4) were transplanted with purified CD4+ T cells from HLA-DR4 negative donors. Taken together, our results demonstrate that IL-10 can profoundly modulate the subset composition and repertoire of responding T cells during GVHD.
