2) Reação do Centro Germinativo

IL-6, IL-21, IL27,

IL-12

Current Opinion in Immunology

Volume 23, Issue 1, February 2011, Pages 111-118
Figure 1. Naïve CD4+ T cells can differentiate into multiple subsets of
effector cells. Cytokines provided by the stimulatory microenvironment
activate specific transcription factors that regulate naïve CD4+ T cell
differentiation. Distinct subsets of effector CD4+ T cells can be
identified by the production of a set of ‘canonical’ cytokines that endow
the cells with specific functions. AHR: aryl hydrocarbon receptor; (h):
human; (m): mouse.
 Cues Guiding Activated T and B cells

Light zone – CXCR4-CXCL12

Light zone – CXCR4-CXCL12

Figure 1. Early during the GC ResponseNaive B cells enter follicles (green shading) guided by CXCR5 expressed on the B
cell, and CXCL13 expressed by the stroma. These cells are CXCR5hi, EBI2+, and CCR7lo. Naive T cells migrate to T zones
(red shading) in response to CCL21. These cells are CCR7hi. Migration of the B cell to and distribution along the T:B zone
border is mediated by the B cells' ability to upregulate CCR7 and EBI2 upon binding antigen (second image from the left).
Primed CD4 T cells upregulate Bcl-6 (orange nucleus) and downregulate CCR7 (second image). B cells receiving T cell help
move to interfollicular regions (third image). After cognate interaction with B cells, T cells maintain high Bcl-6, upregulate
CXCR5, and colocalize with B cells in interfollicular regions (third image). At these sites, some B cells upregulate Bcl-6.
These cells then downregulate EBI2 and cluster at the follicle center (fourth image). Tfh cells migrate through the follicle
and GC light zone (fourth image).

Dark zone – CXCL13 (CXCR5) Light zone – CXCR4-CXCL12

Immunity 35, nov 2011
Cellular and molecular regulation of TFH cell formation

Tcell-Bcell border

Nat Rev immunol

 Tfh and GC Tfh Cell Development

IL-6, ICOSL

Survival and
selection
CD40-CD40L signals

Vaccination efficay

5% GC cells are LT, 1/3 are engaged in long cognate interactions with GC Bcells

Figure 2. T cells primed by DCs can express Bcl-6 soon after CD28-mediated priming under the influence of cytokines
such as IL-12 in humans. Polarization into Bcl-6- versus Blimp-1-expressing cells can be observed as early as after the
first cell division. Differentiation into Tfh cells—CCR7lo CXCR5+ PD-1+ ICOS+ IL-2Rαlo—occurs soon after that, prior
to B cell interaction, and is enhanced by ICOS signaling. By contrast, IL-2 signaling promotes Blimp-1 expression in non-
Tfh cells, which upregulate IL-2Rα expression. Bcl-6 expressing Tfh cells prime B cells for both GC and extrafollicular
plasma cell responses. Cognate interaction with B cells stabilizes Bcl-6 expression—possibly coinciding with a reported
“second wave” of Bcl-6 expression by Tfh cells at their fifth cell division. Highly and stably expressed Bcl-6 in Tfh
cells is important for optimal downregulation of CCR7 and PSGL-1 and upregulation of CXCR5 and SAP, all of which
are required for follicular entry and “residence” as GC Tfh cells. Within germinal centers, GC Tfh cells provide GC B
cells that have taken up antigen held on follicular dendritic cells (FDCs), with growth and survival signals such as IL-21.
Tfh-derived IL-21 and/or IL-6 of stromal origin also appear to be important for maintaining Tfh cells.

Immunity 35, nov 2011