IL-21 boosts germinal center response through independent actions on T and B cells in a concentration-dependent manner
Mariana C.G Miranda Waldetario1,2
1Icahn School of Medicine at Mount Sinai, Jaffe Food Allergy Institute, New York, New York, USA
2Icahn School of Medicine at Mount Sinai, Precision Immunology Institute, New York, New York, USA
Acknowledgments
I would like to thank Dr. Maria A. Curotto de Lafaille for critically review this manuscript and Dr. Anna Globinska for the figures design.
Germinal centers (GC) are the sites of B cell clonal expansion, somatic hypermutation and clonal selection, a process that leads to the production of antibodies of higher affinity 1. Efforts have been made to understand the kinetic of events controlling the GC and the production of specific antibodies in protective as well in pathogenic responses, such as autoimmunity and allergy. The ability of newly mutated GC clones to capture and present antigen to T follicular helper cells (Tfh) in the light zone of the GC is crucial for clonal survival and selection. Tfh cells produce IL-21, a key cytokine for the GC reaction and antibody responses 2. However, it was not understood how IL-21 acts independently on T and B cells to mediate the GC reaction. In this study Quast and colleagues 3contribute to elucidate the specific role of IL-21 on the GC reaction and how IL-21 bioavailability affects the outcome of the GC response. They demonstrate that IL-21 influences Tfh cell differentiation and expansion early, before the GC establishment, as well later during GC development, through both autocrine and paracrine mechanisms, regardless of cognate T-B cell interactions.
The lack of IL-21 signaling profoundly affects the GC persistence and output, resulting in reduced Tfh cell differentiation, B cell expansion, affinity maturation and plasma cell differentiation4,5
The intricate nature of the GC makes it challenging to precisely determine the direct and indirect effects of IL-21 on each component of the GC reaction.
To specifically modulate the IL-21 production (T cells) and sensing (T and B cells) in the GC, Quast and colleagues3 used a mouse model in which mice deficient in both IL-21R and IL-21 received adoptively transferred IL-21R sufficient (Il21r+/+ ) or deficient (Il21r-/- ) hen egg lysozyme (HEL) specific B cells, together with ovalbumin (OVA)-specific IL-21 sufficient (Il21Gfp/+ ) or IL-21 deficient (Il21Gfp/Gfp ) T cells. Following by immunization with cross linked HEL2 x OVApep, resulting in a robust splenic GC response (Fig. 1). Alone, Il21Gfp/Gfp T cells had poor proliferation and Tfh differentiation, but when transferred together with Il21Gfp/+ T cells, both IL-21 competent and IL-21 deficient T cells expanded similarly in the first days following immunization. These results suggested that IL-21 in autocrine or paracrine manner controlled the differentiation and expansion of Tfh cells. This was independent of B cells responding or not to IL-21. Moreover, higher proportion of T secreting IL-21, which increased IL-21 availability in the microenvironment, directly impacted Tfh density and consequently, the magnitude of the GC responses (Fig. 1).