SARS-CoV-2 spike-specific memory B cells express higher levels of T-bet and FcRL5 after non-severe COVID-19 as compared to severe disease

Abstract

SARS-CoV-2 infection elicits a robust B cell response, resulting in the generation of long-lived plasma cells and memory B cells. Here, we aimed to determine the effect of COVID-19 severity on the memory B cell response and characterize changes in the memory B cell compartment between recovery and five months post-symptom onset. Using high-parameter spectral flow cytometry, we analyzed the phenotype of memory B cells with reactivity against the SARS-CoV-2 spike protein or the spike receptor binding domain (RBD) in recovered individuals who had been hospitalized with non-severe (n = 8) or severe (n = 5) COVID-19. One month after symptom onset, a substantial proportion of spike-specific IgG+ B cells showed an activated phenotype. In individuals who experienced non-severe disease, spike-specific IgG+ B cells showed increased expression of markers associated with durable B cell memory, including T-bet and FcRL5, as compared to individuals who experienced severe disease. While the frequency of T-bet+ spike-specific IgG+ B cells differed between the two groups, these cells predominantly showed an activated switched memory B cell phenotype in both groups. Five months post-symptom onset, the majority of spike-specific memory B cells had a resting phenotype and the percentage of spike-specific T-bet+ IgG+ memory B cells decreased to baseline levels. Collectively, our results highlight subtle differences in the B cells response after non-severe and severe COVID-19 and suggest that the memory B cell response elicited during non-severe COVID-19 may be of higher quality than the response after severe disease.

Fate and plasticity of SARS-CoV-2-specific B cells during memory and recall response in humans

“…Moreover, these cells share certain features of so-called age-associated B cells found in mice, which are also characterized by high expression of CD11c and T-bet and implicated in autoimmunity 46,47 . Recently, influenza-specific atypical MBCs have been described transiently during de novo, but not recall, influenza vaccine responses 16 , as well as during acute SARS-CoV-2 infection and vaccination 27,[31][32][33][34][35] , the latter of which is in line with our findings. Intriguingly, we find that SARS-CoV-2-specific atypical MBCs are transcriptionally very similar to their counterparts in autoimmune disease.…”

“…Conversely, CD21 -CD27atypical MBCs have been found in chronic infection, immunodeficiency, and autoimmune diseases where they are thought to be of extrafollicular origin [19][20][21][22][23][24][25] . CD21 -CD27 + activated and CD21 -CD27atypical antigenspecific MBCs have been detected transiently after different vaccines 15,16,18,26,27 and during infections with certain pathogens 26,[28][29][30] , including acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [31][32][33][34][35] . Atypical MBCs are characterized by expression of the transcription factor T-bet, which is essential for their development, as well as high abundance of CD11c and several inhibitory coreceptors, such as Fc receptor-like (FcRL) protein 5 (FcRL5) [36][37][38] .…”

Atypical B cells consist of subsets with distinct effector functions

“…In contrast, nearly all MPS1/AMA1-specific atypical B cells in all three subsets expressed CD95, which was an increase as compared to all atypical B cells. Increased CD95 expression was also observed in Spike-specific B cells in recovered COVID-19 patients ( 39 ) and suggests that these cells recently underwent antigen- driven activation. Collectively, these results suggest that all three subsets of atypical B cells develop in response to antigen stimulation.…”

Autoantibodies elicited with SARS-CoV-2 infection are linked to alterations in double negative B cells

“…In support of this, a decreased frequency of RBD-specific DN2 cells was observed 10 weeks post-infection when compared to levels during acute infection ( 22 ), suggesting that expansion of virus-specific DN2 cells is transient and resolves with infection. However, it should be noted that even five months post-recovery from severe infection, RBD-specific Double Negative B cells are still detectable ( 40 ), indicating that expansion of virally-associated DN subsets likely contracts with infection but are not lost. Furthermore, expansion of atypical memory B cells (CD27 – CD21 lo/– ), which would include both DN2 and DN3 subsets, is resolved in patients recovered from severe SARS-CoV-2 infection ( 41 , 42 ).…”