New perspectives on the regulation of germinal center reaction via αvβ8- mediated activation of TGFβ

Abstract

Transforming growth factor-β (TGFβ) is a long-known modulator of immune responses but has seemingly contradictory effects on B cells. Among cytokines, TGFβ has the particularity of being produced and secreted in a latent form and must be activated before it can bind to its receptor and induce signaling. While the concept of controlled delivery of TGFβ signaling via α_vβ8 integrin-mediated activation has gained some interest in the field of mucosal immunity, the role of this molecular mechanism in regulating T-dependent B cell responses is just emerging. We review here the role of TGFβ and its activation, in particular by α_vβ8 integrin, in the regulation of mucosal IgA responses and its demonstrated and putative involvement in regulating germinal center (GC) B cell responses. We examine both the direct effect of TGFβ on GC B cells and its ability to modulate the functions of helper cells, namely follicular T cells (Tfh and Tfr) and follicular dendritic cells. Synthetizing recently published works, we reconcile apparently conflicting data and propose an innovative and unified view on the regulation of the GC reaction by TGFβ, highlighting the role of its activation by α_vβ8 integrin.

Keywords: IgA B cell response; TGFβ activation; alpha(v)-beta8 integrin (αvβ8); follicular T helper cells (Tfh); follicular dendritic cell (FDC); follicular regulatory helper T cell (Tfr); germinal center (GC) reaction.

Figure 1

α_vβ8 integrins regulate TGFβ bioavailability in the immune system. TGFβ is produced by cells as an inactive complex and must be activated in order to bind to its receptor and signal. (A) Transcription of TGFβ produces a homodimeric propeptide containing the active TGFβ molecule (blue) and the Latent Associated Peptide (LAP; in red). In the endoplasmic reticulum, association with the LTBP or GARP ‘chaperone’ proteins (green) enhances proper folding of the latent complex. In the Golgi apparatus, LAP-TGFβ is cleaved by Furin-like enzymes, but active TGFβ stays non-covalently bound to the LAP and forms the Small Latency Complex or latent TGFβ (79) (B) Upon secretion, latent TGFβ is sequestered to the ECM through binding of the LTBP or anchored at the plasma membrane by GARP. (C) Binding of α_v integrins to the RGD tripeptide motif in the LAP induces the dissociation of TGFβ from the LAP via the recruitment of metalloproteases such as MMP14 (78). Alternatively, conformational changes can allow TGFβ binding to its receptor without the release of active TGFβ (80). (D) TGFβ binding to the TGFβ receptor induces signaling via the canonical phospho-Smad (pSmad) pathway, or through the alternative MAPK, Small GTPases and PIP3K pathways.

Figure 2

Demonstrated and putative roles of α_vβ8-mediated activation of TGFβ in the regulation of mucosal IgA responses. (A) At steady state, Reboldi and colleagues suggest that α_vβ8 expression by Peyer’s Patches CD103⁺ cDC is required for the induction of IgA response to the commensal flora (122). Additionally, TGFβ activation by FDC through mechanisms yet to be determined might also be a mechanism for the promotion of IgA response in the PP (123) (B) In the context of intestinal rotavirus infection, MLN cDC1, migrating from the LP, are required for optimal RV-specific IgA response, in part promoted via α_vβ8-mediated activation of TGFβ (124). (C) In lung-draining LN, the ability of individual cDC subpopulation to induce IgA response to microbiota via TGFβ production is correlated with their expression of the Itgb8 transcript (125). (D) Despite lack of formal demonstration, we propose that, given their molecular arsenal and TGFβ-dependent function in the intestinal mucosae, α_vβ8-expressing Foxp3⁺ T cells (Treg) could activate GARP-bound TGFβ on B cells for induction of IgA responses (104, 110). More generally, the expression of GARP-TGFβ complexes by B cells suggest that activated B cells themselves could be a physiologically relevant source of latent TGFβ (126, 127).

Figure 3

Model for the regulation of the GC reaction via the controlled delivery of active TGFβ by α_vβ8 integrin. (A) TGFβ signaling in FDC may promote their survival and cytokine production and as such indirectly supports the GC reaction. In addition, given their expression of TGFβ activating molecule, mucosal FDC themselves are a likely source of active TGFβ (123). Furthermore, Albright and colleagues provided evidence that TGFβ produced by FDC may be important for LZ to DZ trafficking of GC B cells. The mechanisms involved may include α_vβ8 although formal demonstration is lacking (31). (B) Evidence suggests that TGFβ is required, at least in certain situations, for the induction of Foxp3⁺ follicular T cells (Tfr) (36, 44, 67). In addition, Tfr may be able to regulate GC B cell responses via α_vβ8-mediated activation of TGFβ (61, 64, 142). (C) α_vβ8-mediated activation of TGFβ by follicular myeloid populations has been involved in the induction of Tfh (143). Additionally, a model in which TGFβ promotes the survival of Tfh in the context of immunization have been proposed (35). In these contexts, the source of active TGFβ is still currently unknown.