B-cell differentiation and IL-21 response in IL2RG/JAK3 SCID patients after hematopoietic stem cell transplantation

Abstract

Allogeneic hematopoietic stem cell transplant (HSCT) typically results in donor T-cell engraftment and function in patients with severe combined immunodeficiency (SCID), but humoral immunity, particularly when using donors other than matched siblings, is variable. B-cell function after HSCT for SCID depends on the genetic cause, the use of pre-HSCT conditioning, and whether donor B-cell chimerism is achieved. Patients with defects in or undergoing HSCT without conditioning often have poor B-cell function post-HSCT, perhaps as a result of impairment of IL-21 signaling in host-derived B cells. To investigate the effect of pre-HSCT conditioning on B-cell function, and the relationship of in vitro B-cell function to clinical humoral immune status, we analyzed 48 patients with SCID who were older than 2 years after HSCT with donors other than matched siblings. T follicular helper cells (T) developed in these patients with kinetics similar to healthy young children; thus, poor B-cell function could not be attributed to a failure of T development. In vitro differentiation of B cells into plasmablasts and immunoglobulin secretion in response to IL-21 strongly correlated with the use of conditioning, donor B-cell engraftment, freedom from immunoglobulin replacement, and response to tetanus vaccine. Patients receiving immunoglobulin replacement who had normal serum immunoglobulin M showed poor response to IL-21 in vitro, similar to those with low serum IgM. In vitro response of B cells to IL-21 may predict clinically relevant humoral immune function in patients with SCID after HSCT.

Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients

“…Combining our defined readouts of cellular function with clinical features after HSCT may facilitate predicting long-term outcomes for DOCK8-deficient patients undergoing potentially curative HSCT. Such an approach has been applied to SCID patients, with several clinical, cellular, and functional improvements being established as predictors of successful outcomes of HSCT (12,79,80). Collectively, our results underscore the value and importance of determining the impact of monogenic mutations on immune cell function and applying these findings following therapeutic interventions in order to ensure optimal patient management and outcomes.…”

Regulation of the germinal center and humoral immunity by interleukin-21

“…A likely role of IL-21R/STAT3 signaling in efficient Ab responses in humans was supported by the finding that B cells with mutations in IL2RG, a component of the IL-21R complex, or the downstream kinase JAK3 phenocopy STAT3 DN B cells with respect to impaired memory cell formation and unresponsiveness to IL-21 (Miggelbrink et al, 2018;Recher et al, 2011; Table 1). Importantly, investigation of SCID patients who had undergone hematopoietic stem cell transplant and engrafted with donor T cells but retained IL2RG mutant B cells established a clear requirement for expression of γc, and by extension IL-21R, by B cells for the successful generation of effective Ag-specific Ab responses (Miggelbrink et al, 2018;Recher et al, 2011; Table 1).…”

“…IL-21-mediated differentiation of naive B cells to these distinct effector fates in vivo is controlled by the balanced expression and function of various transcription factors, including (but not exclusively) PAX5, BCL-6, BLIMP-1, XBP-1, and IRF4. The generation of memory B cells and PCs secreting high-affinity Ig is compromised by DN mutations in STAT3 (Avery et al, 2010;Deenick et al, 2013) and also by AR mutations in ZNF341 (Béziat et al, 2018;Frey-Jakobs et al, 2018) or IL21R or hemizygous mutations in IL2RG (Miggelbrink et al, 2018;Recher et al, 2011). IL-21 derived from Tfh cells was responsible for CD4 + TD B cell differentiation into Ig-secreting cells in vitro (Avery et al, 2008;Bryant et al, 2007;Kuchen et al, 2007;Ma et al, 2009). Notably, most Tfh cells in human tonsils that express IL-4 also expressed IL-21 (Ma et al, 2009), revealing Tfh cells as a source of cytokines well characterized for B cell activation (Moens and Tangye, 2014).…”

Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID

“…This discrepancy is attributed to the ability of IL-4 to bind and signal through either a receptor comprising γc and IL-4RA or an alternate receptor comprising IL-4RA and IL-13R chains. On the other hand, γc is indispensable for IL-21 signaling (5,13,15). We found our patient's T cells showed normal γc signaling (Figure 2A).…”

“…Long-lived protective antibody responses and the formation of memory B cells are dependent on IL-21 signaling through a normal γc (5,15,26). In post-transplant patients, at least 10% of B cells must have adequate IL-21 signaling for B cells to function (5,15).…”