IgM Memory Cells: First Responders in Malaria
Authors: Sara L. Stone, Frances E. Lund
Journal: Immunity (2016)

Following the fate of antigen-specific memory B cells has been difficult. In this issue of Immunity, Krishnamurty et al., 2016Krishnamurty A.T. Thouvenel C.D. Portugal S. Keitany G.J. Kim K.S. Holder A. Crompton P.D. Rawlings D.J. Pepper M. Immunity. 2016; 45 (this issue): 402-414Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar use a novel B cell tetramer to define Plasmodium-specific memory B cells in parasite-infected mice and demonstrate that after re-infection, somatically mutated IgM+ memory B cells function as first responders by rapidly differentiating into T-cell-dependent plasmablasts and T-cell-independent plasma cells. Following the fate of antigen-specific memory B cells has been difficult. In this issue of Immunity, Krishnamurty et al., 2016Krishnamurty A.T. Thouvenel C.D. Portugal S. Keitany G.J. Kim K.S. Holder A. Crompton P.D. Rawlings D.J. Pepper M. Immunity. 2016; 45 (this issue): 402-414Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar use a novel B cell tetramer to define Plasmodium-specific memory B cells in parasite-infected mice and demonstrate that after re-infection, somatically mutated IgM+ memory B cells function as first responders by rapidly differentiating into T-cell-dependent plasmablasts and T-cell-independent plasma cells. Memory B cells (MBCs) and long-lived plasma cells (LLPCs) are responsible for enduring humoral immunity and are the targets of most vaccines (Kurosaki et al., 2015Kurosaki T. Kometani K. Ise W. Nat. Rev. Immunol. 2015; 15: 149-159Crossref PubMed Scopus (411) Google Scholar). Although LLPCs can be easily enumerated, it has been challenging to identify antigen-specific MBCs, particularly those induced after infection. This has constrained our ability both to phenotype MBCs and to determine which MBC populations are durable and protective. In this issue of Immunity, Krishnamurty et al., 2016Krishnamurty A.T. Thouvenel C.D. Portugal S. Keitany G.J. Kim K.S. Holder A. Crompton P.D. Rawlings D.J. Pepper M. Immunity. 2016; 45 (this issue): 402-414Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar have used a novel “B cell tetramer” reagent to identify mouse and human MBCs specific to MSP1 expressed by Plasmodium—the pathogen that causes malaria. Challenge infections in mice revealed unique functions and requirements for immunoglobulin M (IgM)+ MBCs. Over the last decade, several laboratories have embarked on the difficult task of characterizing murine MBC subsets (Kurosaki et al., 2015Kurosaki T. Kometani K. Ise W. Nat. Rev. Immunol. 2015; 15: 149-159Crossref PubMed Scopus (411) Google Scholar). These studies were frequently performed with vaccine and adoptive-transfer approaches with transgenic B cells. These analyses revealed significant heterogeneity in the developing MBC populations, leading to speculation that specific phenotypic characteristics of the quiescent MBCs, such as the B cell receptor (BCR) isotype, might predict their future functional attributes. Indeed, adoptive-transfer experiments have revealed divergent functions of MBC populations after recall. For example, some groups demonstrated that unswitched (IgM+) MBCs preferentially seeded secondary germinal centers (GCs) and that isotype-switched (IgM−) MBCs preferentially differentiated into plasmablasts (PBs) (Dogan et al., 2009Dogan I. Bertocci B. Vilmont V. Delbos F. Mégret J. Storck S. Reynaud C.-A. Weill J.-C. Nat. Immunol. 2009; 10: 1292-1299Crossref PubMed Scopus (434) Google Scholar, Pape et al., 2011Pape K.A. Taylor J.J. Maul R.W. Gearhart P.J. Jenkins M.K. Science. 2011; 331: 1203-1207Crossref PubMed Scopus (382) Google Scholar). Other groups either observed the converse (McHeyzer-Williams et al., 2015McHeyzer-Williams L.J. Milpied P.J. Okitsu S.L. McHeyzer-Williams M.G. Nat. Immunol. 2015; 16: 296-305Crossref PubMed Scopus (158) Google Scholar) or reported that MBC commitment to the PB or GC fate is best predicted by whether the MBCs express CD80, PDL2, and/or CD73, irrespectively of the BCR isotype (Anderson et al., 2007Anderson S.M. Tomayko M.M. Ahuja A. Haberman A.M. Shlomchik M.J. J. Exp. Med. 2007; 204: 2103-2114Crossref PubMed Scopus (190) Google Scholar, Zuccarino-Catania et al., 2014Zuccarino-Catania G.V. Sadanand S. Weisel F.J. Tomayko M.M. Meng H. Kleinstein S.H. Good-Jacobson K.L. Shlomchik M.J. Nat. Immunol. 2014; 15: 631-637Crossref PubMed Scopus (249) Google Scholar). Collectively, these data suggest that we have yet to find a set of parameters that can accurately capture the full complexity of the MBC pool. Krishnamurty et al., 2016Krishnamurty A.T. Thouvenel C.D. Portugal S. Keitany G.J. Kim K.S. Holder A. Crompton P.D. Rawlings D.J. Pepper M. Immunity. 2016; 45 (this issue): 402-414Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar have taken a new approach to addressing heterogeneity in the MBC compartment. The authors transferred P. chabaudi-infected RBCs into mice and used MSP1 tetramers to track MSP1+ B cells. They identified multiple MSP1+ populations, including putative CD38+ MBCs, which expanded over 2 weeks and then contracted to a set point that was elevated over pre-infection levels. Approximately 20% of the MSP1+CD38+ MBCs were IgM+, and 30% were isotype switched (IgM−). The remaining MSP1+ B cells expressed IgD (IgD+ MBCs). Although more MSP1+IgD+ B cells were found in the spleens of mice that had recovered from a prior P. chaubadi infection (memory mice) than in the spleens of naive controls, the BCRs of these B cells were not mutated, and the cells did not express memory cell marker CD73 or CD80, suggesting that the IgD+ MBCs might represent an expanded pool of MSP1+ “naive-like” precursors. By contrast, both IgM+ and IgM− MSP1+ B cells exhibited MBC hallmarks given that they were largely CD80+CD73+ and expressed somatically mutated BCRs. Interestingly, ELISA analysis revealed that recombinant antibodies (Abs) generated from the BCRs expressed by the IgM+ and IgM− MBC subsets bound MSP1 with similar affinity, suggesting that both types of MBCs might be functionally important. Re-infection of memory mice led to a rapid boost in serum MSP1-specific Ab levels and in the numbers of MSP1+ PBs, plasma cells (PCs), GC precursors, and MBCs. On day 3 after challenge, the majority of MSP1-specific PBs and PCs expressed IgM, and serum levels of MSP1-specific IgM, but not IgG, were increased. Sequencing of the BCRs from day 3 IgM+ PBs and PCs suggested that these cells were most likely derived from a mutated IgD− MBC subset. By day 5 after challenge, both IgM− and IgM+ MSP1-specific Ab-secreting cells (ASCs) were detected at similar levels. Enzyme-linked immunospot (ELISPOT) analysis of in-vitro-cultured IgM+ MBCs isolated 2 days after challenge suggested that IgM+ MBCs could seed both IgM+ and IgG+ ASCs. The faster response of the IgM+ MBCs to rechallenge infection than of the IgM− MBCs was not due to pathogen dose or timing of the re-infection, nor was it due to a differential reliance on T cell help. Instead, the data argue that the P. chabaudi-specific IgM+ MBCs effectively competed with the IgM− MBC pool and rapidly generated two distinct ASC populations—a proliferating T-cell-dependent PB population and a T-cell-independent terminally differentiated PC population (Figure 1). Krishnamurty et al., 2016Krishnamurty A.T. Thouvenel C.D. Portugal S. Keitany G.J. Kim K.S. Holder A. Crompton P.D. Rawlings D.J. Pepper M. Immunity. 2016; 45 (this issue): 402-414Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar demonstrate that both IgM+ and IgM− MBCs can differentiate into ASCs after challenge infection with P. chabaudi. These data could help span the divide over the question of whether the MBC isotype dictates their fate choice after antigen re-exposure (Anderson et al., 2007Anderson S.M. Tomayko M.M. Ahuja A. Haberman A.M. Shlomchik M.J. J. Exp. Med. 2007; 204: 2103-2114Crossref PubMed Scopus (190) Google Scholar, Dogan et al., 2009Dogan I. Bertocci B. Vilmont V. Delbos F. Mégret J. Storck S. Reynaud C.-A. Weill J.-C. Nat. Immunol. 2009; 10: 1292-1299Crossref PubMed Scopus (434) Google Scholar, Pape et al., 2011Pape K.A. Taylor J.J. Maul R.W. Gearhart P.J. Jenkins M.K. Science. 2011; 331: 1203-1207Crossref PubMed Scopus (382) Google Scholar, Zuccarino-Catania et al., 2014Zuccarino-Catania G.V. Sadanand S. Weisel F.J. Tomayko M.M. Meng H. Kleinstein S.H. Good-Jacobson K.L. Shlomchik M.J. Nat. Immunol. 2014; 15: 631-637Crossref PubMed Scopus (249) Google Scholar, McHeyzer-Williams et al., 2015McHeyzer-Williams L.J. Milpied P.J. Okitsu S.L. McHeyzer-Williams M.G. Nat. Immunol. 2015; 16: 296-305Crossref PubMed Scopus (158) Google Scholar). The data also help clarify the issue of whether secondary MBC responses are T cell dependent (Kurosaki et al., 2015Kurosaki T. Kometani K. Ise W. Nat. Rev. Immunol. 2015; 15: 149-159Crossref PubMed Scopus (411) Google Scholar), given that the ASC response following P. chabaudi challenge appears to be layered—with respect to both the kinetics and the T cell dependence of the response. The data also argue that IgM+ MBCs are key players early after challenge infection. Not only do the IgM Abs made by the ASC progenitors of IgM+ MBCs have an affinity similar to that of Abs derived from IgG+ MBCs, but the secreted pentameric IgM Abs also have the added benefits of higher avidity binding to P. chabaudi target antigens and efficient complement fixation. Because complement-mediated lysis is important for blood-stage infection control (Boyle et al., 2015Boyle M.J. Reiling L. Feng G. Langer C. Osier F.H. Aspeling-Jones H. Cheng Y.S. Stubbs J. Tetteh K.K.A. Conway D.J. et al.Immunity. 2015; 42: 580-590Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar), IgM+ MBCs appear poised to promote early parasite clearance. The identification of MSP1-specific IgM+ and IgM− MBC populations in humans is exciting given that the induction of MSP1-specific IgM and IgG antibodies correlates with clinical immunity in patient populations (Arama et al., 2015Arama C. Skinner J. Doumtabe D. Portugal S. Tran T.M. Jain A. Traore B. Doumbo O.K. Davies D.H. Troye-Blomberg M. et al.Open Forum Infect. Dis. 2015; 2: ofv118Crossref PubMed Google Scholar). In humans, primary infection with malaria rarely leads to protection, and persistently elevated IgG titers are achieved only after years of repeated exposure (Portugal et al., 2013Portugal S. Pierce S.K. Crompton P.D. J. Immunol. 2013; 190: 3039-3046Crossref PubMed Scopus (85) Google Scholar). Thus, MBCs could be particularly important mediators of anti-malarial immunity, especially given the variability of antigens present in different strains and blood stages of P. chabaudi. Few studies have tracked MBC development and recall responses following pathogen exposure. Because pathogens can replicate in specific host tissues and can express complex antigens and TLR ligands that are present for months after infection, it is likely that the MBCs that develop and are reactivated will be exquisitely tailored to the pathogen and that pathogen-specific MBCs will come in many flavors. The study by Krishnamurty et al., 2016Krishnamurty A.T. Thouvenel C.D. Portugal S. Keitany G.J. Kim K.S. Holder A. Crompton P.D. Rawlings D.J. Pepper M. Immunity. 2016; 45 (this issue): 402-414Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar is an important addition to the MBC field because it provides the first taste of the complex cocktail of MBCs that arise in response to a parasite that infects >300 million individuals worldwide. Somatically Hypermutated Plasmodium-Specific IgM+ Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria RechallengeKrishnamurty et al.ImmunityJuly 26, 2016In BriefHeterogeneous types of memory B cells are present in both humans and mice, yet it is unclear how different MBC subsets form or function in response to infection. Pepper and colleagues reveal that phenotypically and functionally distinct populations of polyclonal Plasmodium-specific MBCs form in response to infection and somatically hypermutated, high-affinity, plastic IgM+ memory B cells dominate the early memory response to malaria rechallenge. Full-Text PDF Open Access