RESUMO
Activation-induced cytidine deaminase (AID), produced by the Aicda gene, is essential for the immunoglobulin gene (Ig) alterations that form immune memory. Using a Cre-mediated genetic system, we unexpectedly found CD4(+) T cells that had expressed Aicda (exAID cells) as well as B cells. ExAID cells increased with age, reaching up to 25% of the CD4(+) and B220(+) cell populations. ExAID B cells remained IgM(+), suggesting that class-switched memory B cells do not accumulate in the spleen. In T cells, AID was expressed in a subset that produced IFN-γ and IL-10 but little IL-4 or IL-17, and showed no evidence of genetic mutation. Interestingly, the endogenous Aicda expression in T cells was enhanced in the absence of B cells, indicating that the process is independent from the germinal center reaction. These results suggest that in addition to its roles in B cells, AID may have previously unappreciated roles in T-cell function or tumorigenesis.
Assuntos
Envelhecimento/sangue , Linfócitos T CD4-Positivos/enzimologia , Citidina Desaminase/sangue , Interleucina-10/biossíntese , Animais , Linfócitos T CD4-Positivos/metabolismo , Citidina Desaminase/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Activation-induced cytidine deaminase (AID) and uracil DNA glycosylase (UNG) are required for class switch recombination (CSR). AID is involved in the DNA cleavage step of CSR, but the precise role of UNG is not yet understood. Mutations and deletions are footprints of abortive DNA cleavage in the immunoglobulin switch region in splenic B cells stimulated to undergo CSR. However, a UNG deficiency did not reduce the number of such footprints, indicating UNG is dispensable for the DNA cleavage step. Mutagenesis experiments revealed that the role of UNG in CSR depends on its WXXF motif. This motif is also essential for the interaction of UNG with the HIV viral peptide Vpr, which recruits UNG to the HIV particle. Furthermore, exogenous Vpr had a dominant-negative effect on CSR. These results suggest that UNG is recruited to the CSR machinery through its WXXF motif by a Vpr-like host factor and plays a novel non-canonical role in a CSR step that follows DNA cleavage.
Assuntos
Recombinação Genética , Uracila-DNA Glicosidase/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Linfócitos B/metabolismo , Genes Dominantes , Hibridomas/metabolismo , Imunoglobulina M/química , Imunoglobulinas/química , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Mutação , Homologia de Sequência de AminoácidosRESUMO
Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic bone marrow transplantation, which is caused by donor T cells specific for host alloantigens. In a murine model, we found that donor T cells expressed a natural killer cell inhibitory receptor, CD94/NKG2A, during the course of aGVHD. Administration of an anti-NKG2A mAb markedly inhibited the expansion of donor T cells and ameliorated the aGVHD pathologies. These results suggested that the CD94/NKG2A inhibitory receptor expressed on host-reactive donor T cells can be a novel target for the amelioration of aGVHD.
