RESUMO
Polarized segregation of proteins in T cells is thought to play a role in diverse cellular functions including signal transduction, migration, and directed secretion of cytokines. Persistence of this polarization can result in asymmetric segregation of fate-determining proteins during cell division, which may enable a T cell to generate diverse progeny. Here, we provide evidence that a lineage-determining transcription factor, T-bet, underwent asymmetric organization in activated T cells preparing to divide and that it was unequally partitioned into the two daughter cells. This unequal acquisition of T-bet appeared to result from its asymmetric destruction during mitosis by virtue of concomitant asymmetric segregation of the proteasome. These results suggest a mechanism by which a cell may unequally localize cellular activities during division, thereby imparting disparity in the abundance of cell fate regulators in the daughter cells.
Assuntos
Mitose , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas com Domínio T/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Polaridade Celular , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteínas com Domínio T/metabolismo , Linfócitos T/enzimologiaRESUMO
Clonal selection of a T cell for use in the immune response appears to necessitate proliferative expansion and terminal effector differentiation of some cellular progeny, while reserving other progeny as less-differentiated memory cells. It has been suggested that asymmetric cell division may promote initial cell diversification. Stem cell-like models of adaptive immunity might predict that subsequent encounters with a pathogen would evoke reiterative, self-renewing, asymmetric division by memory T cells. In this study, we show that murine memory CD8(+) T cells can divide asymmetrically in response to secondary encounter with pathogen. Critical regulators of signaling and transcription are partitioned to one side of the mitotic spindle in rechallenged memory T cells, and two phenotypically distinct populations of daughter cells are evident from the earliest divisions. Memory T cells may thus use asymmetric cell division to generate cellular heterogeneity when faced with pathogen rechallenge.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Divisão Celular/imunologia , Memória Imunológica , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Transdução de Sinais/imunologia , Animais , Divisão Celular/genética , Coriomeningite Linfocítica/genética , Camundongos , Camundongos Transgênicos , Transdução de Sinais/genética , Transcrição Gênica/genética , Transcrição Gênica/imunologiaRESUMO
Lifelong antibody responses to vaccination require reorganization of lymphoid tissue and dynamic intercellular communication called the germinal center reaction. B lymphocytes undergo cellular polarization during antigen stimulation, acquisition, and presentation, which are critical steps for initiating humoral immunity. Here, we show that germinal center B lymphocytes asymmetrically segregate the transcriptional regulator Bcl6, the receptor for interleukin-21, and the ancestral polarity protein atypical protein kinase C to one side of the plane of division, generating unequal inheritance of fate-altering molecules by daughter cells. Germinal center B lymphocytes from mice with a defect in leukocyte adhesion fail to divide asymmetrically. These results suggest that motile cells lacking constitutive attachment can receive provisional polarity cues from the microenvironment to generate daughter cell diversity and self-renewal.