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Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses
H Nishimura1, N Minato, T Nakano
1Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Japan.
Insights
Mice lacking Programmed cell Death protein 1 (PD-1) showed increased B cell proliferation and antibody production, particularly IgG3. This suggests PD-1 negatively regulates certain B cell responses, including class switching.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Programmed cell Death protein 1 (PD-1) is an inhibitory receptor expressed on lymphocytes.
- Its role in regulating immune responses, particularly B cell function, is not fully understood.
Purpose of the Study:
- To investigate the function of PD-1 in immune responses.
- To characterize the immune phenotype of PD-1-deficient mice.
Main Methods:
- Generation of PD-1-deficient (PD-1-/-) mice using gene-targeting.
- Analysis of splenomegaly, lymphocyte cellularity, and B cell proliferation in vitro.
- Measurement of serum immunoglobulin levels and antibody responses to T-independent antigens.
Main Results:
- PD-1-/- mice exhibited splenomegaly with increased lymphoid and myeloid cellularity.
- Enhanced B cell proliferation and augmented serum levels of IgG2b, IgA, and IgG3 were observed.
- Increased IgG3 antibody response to DNP-Ficoll and reduced CD5 expression on peritoneal B-1 cells were noted.
Conclusions:
- PD-1 plays a role in the negative regulation of B cell proliferation and differentiation.
- The absence of PD-1 leads to enhanced antibody class switching, particularly to IgG3.
Abstract:
PD-1, an Ig superfamily member, contains an immunoreceptor tyrosine-based inhibitory motif in the cytoplasmic tail. It is expressed in a minor fraction of CD4-CD8- normal thymocytes and induced in peripheral lymphocytes following activation. To assess the possible roles of PD-1 in the immune responses, PD-1-deficient (PD-1-/-) mice were generated by a gene-targeting strategy. PD-1-4- mice developed and grew normally. Although the thymus was apparently normal, PD-1-/- mice showed moderate but consistent splenomegaly, which reflected the increased cellularity of both lymphoid and myeloid cells. The proliferative response of B cells by anti-IgM antibodies, but not of T cells by an anti-CD3 (145-2C11) mAb in vitro, was augmented in PD-1-/- mice as compared with control littermates. PD-1-/- mice showed increased serum levels of IgG2b, IgA and most strikingly IgG3, while those of IgM and IgG1 were comparable with control mice. Furthermore, PD-1-/- mice exhibited significantly augmented IgG3 anti-DNP antibody response to a type 2 T-independent antigen, DNP-Ficoll, with comparable IgM and IgG1 antibody responses with littermate controls. In the peritoneal cavity, the B-1 cell population in PD-1-/- mice exhibited significantly reduced expression of CD5, a negative regulator of B-1 cell activation, despite a marginal increase in the number of B-1 cells. Thus, PD-1 was suggested to be involved in the negative regulation for particular aspects of B cell proliferation and differentiation including class switching.
