RESUMO
Lymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. Lymphocyte homing to lymph nodes peaked at night onset, with cells leaving the tissue during the day. This resulted in strong oscillations in lymphocyte cellularity in lymph nodes and efferent lymphatic fluid. Using lineage-specific genetic ablation of circadian clock function, we demonstrated this to be dependent on rhythmic expression of promigratory factors on lymphocytes. Dendritic cell numbers peaked in phase with lymphocytes, with diurnal oscillations being present in disease severity after immunization to induce experimental autoimmune encephalomyelitis (EAE). These rhythms were abolished by genetic disruption of T cell clocks, demonstrating a circadian regulation of lymphocyte migration through lymph nodes with time-of-day of immunization being critical for adaptive immune responses weeks later.
Assuntos
Imunidade Adaptativa/imunologia , Quimiotaxia de Leucócito/imunologia , Relógios Circadianos/imunologia , Vigilância Imunológica/imunologia , Linfócitos/imunologia , Transferência Adotiva , Animais , Encefalomielite Autoimune Experimental/imunologia , Citometria de Fluxo , Imunofluorescência , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
T cells are sequestered for several days in lymph nodes following antigen recognition but the precise mechanism regulating their timing of egress is not fully understood. In particular, whether interactions with antigen-presenting cells (APCs) and/or strength of the TCR stimulation shape T-cell residence time is unclear. We report here that the probability of T-cell egress decreases upon stimulation with high affinity TCR ligands. In contrast, low affinity peptides favor early egress, a phenomenon that could be reversed by sustaining antigen availability. The delayed egress of high affinity T cells could not be accounted by physical sequestration by APCs. Instead, we found that the sphingosine-1-phosphate receptor (S1P1 ) downregulation mirrors the strength and persistence of the TCR stimulation, limiting egress of high affinity T cells. We propose that S1P1 acts as a rheostat to tailor T-cell residence time in the lymph node to the local availability of antigen and to optimize the expansion of high affinity T cells.