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).