Differential effect of HLA class-I versus class-II transgenes on human T and B cell reconstitution and function in NRG mice.
Humanized mice expressing Human Leukocyte Antigen (HLA) class I or II transgenes have been generated, but the role of class I vs class II on human T and B cell reconstitution and function has not been investigated in detail. Herein we show that NRG (NOD.RagKO.IL2RγcKO) mice expressing HLA-DR4 molecules (DRAG mice) and those co-expressing HLA-DR4 and HLA-A2 molecules (DRAGA mice) did not differ in their ability to develop human T and B cells, to reconstitute cytokine-secreting CD4 T and CD8 T cells, or to undergo immunoglobulin class switching. In contrast, NRG mice expressing only HLA-A2 molecules (A2 mice) reconstituted lower numbers of CD4 T cells but similar numbers of CD8 T cells. The T cells from A2 mice were deficient at secreting cytokines, and their B cells could not undergo immunoglobulin class switching. The inability of A2 mice to undergo immunoglobulin class switching is due to deficient CD4 helper T cell function. Upon immunization, the frequency and cytotoxicity of antigen-specific CD8 T cells in DRAGA mice was significantly higher than in A2 mice. The results indicated a multifactorial effect of the HLA-DR4 transgene on development and function of human CD4 T cells, antigen-specific human CD8 T cells, and immunoglobulin class switching.
US Military Malaria Vaccine Program, Naval Medical Research Center/Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Sai
S
Majji
US Military Malaria Vaccine Program, Naval Medical Research Center/Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Wathsala
W
Wijayalath
US Military Malaria Vaccine Program, Naval Medical Research Center/Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Soumya
S
Shashikumar
Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
Luis
L
Pow-Sang
US Military Malaria Vaccine Program, Naval Medical Research Center/Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Eileen
E
Villasante
Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
Teodor D
TD
Brumeanu
US Military Malaria Vaccine Program, Naval Medical Research Center/Walter Reed Army Institute of Research, Silver Spring, MD, USA.|Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
Sofia
S
Casares
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000235:genetics*; D015804:HLA-DR4 Antigen / Q000235:genetics*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D009980:Influenza A virus / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000138:chemical synthesis / Q000276:immunology
D016207:Cytokines; D015789:HLA-A2 Antigen; D015804:HLA-DR4 Antigen; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010455:Peptides; D014764:Viral Proteins