Intrinsic features of the CD8α− dendritic cell subset in inducing functional T follicular helper cells

Abstract

T follicular helper (Tfh) cells, a true B cell helper, have a critical role in enhancing humoral immune responses. However, the initial differentiation of Tfh cells by dendritic cells (DCs), the most potent antigen presenting cells, has not been clearly understood, particularly in the knowledge of the two major conventional dendritic cell subsets, CD8α(+) DCs or CD8α(-) DCs. Here we demonstrated that the localization of CD8α(-) DCs in the marginal zone (MZ) bridging channels is closely associated with the induction of CXCR5(+)CCR7(low) Tfh cells. We also showed that the major source of IL-6 for inducing Tfh cells is provided from the activated CD4(+) T cells induced by CD8α(-) DCs, and IL-6 directly secreted from the DC subsets seems minor. CD8α(-) DCs were superior in inducing functional Tfh cells over other antigen presenting cells including B cells. We here observed the unknown intrinsic features of the DC subsets, suggesting the potential of utilizing the CD8α(-) DC subset as therapeutic vaccine for the regulation of humoral immune responses.

Distinct oxysterol requirements for positioning naïve and activated dendritic cells in the spleen

“…Although they have been established to augment Tfh cell differentiation and antibody responses (1, 18, 38), they also support IFNγ-producing T cell responses (39, 40). Because type I IFN is most prominently induced during infections with intracellular pathogens, perhaps dispersal throughout the T cell zone allows the cDC2s to present antigen in a manner that more effectively induces a T helper 1 cell fate.…”

Treatment of spontaneous EAE by laquinimod reduces Tfh, B cell aggregates, and disease progression

“… 17 Previously, we demonstrated that in vivo laquinimod treatment causes a disproportionate reduction in the numbers of the CD11c + CD4 + CD8α − (referred to as CD4 + ) dendritic cells (DCs). 5 The CD4 + DC subpopulation is instrumental in promoting differentiation of T follicular helper (Tfh) cells, 18 – 20 the CD4 + T cell subset that directs B cell differentiation, germinal center (GC) formation, and immunoglobulin (Ig) class switching. 21 Therefore, we hypothesized that laquinimod could affect several B cell activities that contribute to CNS autoimmunity.…”

Mecanismo de geração de resposta imune humoral induzida pelo direcionamento do antígeno MSP1₁₉PADRE para duas populações distintas de células dendríticas via receptores DEC205 e DCIR2.

“…As DCs CD8αtambém estão presentes no baço e nos linfonodos de camundongos mas, diferentemente das DCs CD8α + , estão localizadas nas zonas marginais às células B na polpa vermelha do baço (SHIN et al, 2016). Estas células, além de serem negativas para a cadeia alfa da molécula CD8, expressam o marcador de superfície CD11b, sendo consideradas cDC2.…”

“…As cDCs2, por exemplo, vem sendo associadas a instrução de células Th17 enquanto que as cDCs1, principalmente as DCs CD8α + , estão relacionadas com a resposta Th1 (SCHLITZER et al, 2013;SOARES et al, 2007). Dessa forma, cada subtipo de DCs especificamente apresenta características intrínsecas a sua própria biologia que garantem a sua especialização na indução de uma polarização de células T CD4 + (SHIN et al, 2016). Essas características podem ser desde a expressão de TLRs e sua ativação frente aos seus ligantes ou, até mesmo, as expressões de diferentes moléculas co-estimulatórias, citocinas, vias de sinalização e fosforilação intracelulares e outros mecanismos dependentes do subtipo de DC (LI et al, 2016;NAPOLITANI et al, 2005;SHIN et al, 2015).…”

“…Ele se liga diretamente no CD40 promovendo o aumento da expressão das moléculas coestimulatórias (BONIFAZ et al, 2004;BOSCARDIN et al, 2006;DUDZIAK et al, 2007;HEATH;HOWARD, 1994). Além disso, ligantes de TLR também são utilizados, sendo o mais frequente o Poly I:C que liga-se nos receptores TLR3 e MDA-5 RAMPAZO;HENRIQUES et al, 2013;RAMPAZO et al, 2015;SHIN et al, 2016;SHIN et al, 2015). Na realidade, a administração de Poly I:C no direcionamento de antígenos via DEC205 tem se mostrado como o melhor adjuvante a ser utilizado na indução de células T CD4 + produtoras de IFN-γ (TEWARI et al, 2010;TRUMPFHELLER et al, 2008).…”