T Cell–Dependent IgM Memory B Cells Generated during Bacterial Infection Are Required for IgG Responses to Antigen Challenge

Abstract

Immunological memory has long considered to be harbored in B cells that express high affinity class-switched IgG. IgM-positive memory B cells can also be generated following immunization, although their physiological role has been unclear. Here we show that bacterial infection elicited a relatively large population of IgM memory B cells that were uniquely identified by their surface expression of CD11c, CD73, and PD-L2. The cells lacked expression of cell surface markers typically expressed by GC B cells, were CD138-negative, and did not secrete antibody ex vivo. The population was also largely quiescent, and accumulated somatic mutations. The IgM memory B cells were located in the region of the splenic marginal zone, and were not detected in blood or other secondary lymphoid organs. Generation of the memory cells was CD4 T cell-dependent, and required IL-21R signaling. In vivo depletion of the IgM memory B cells abrogated the IgG recall responses to specific antigen challenge, demonstrating that the cell population was required for humoral memory, and underwent class switch recombination following antigen encounter. Our findings demonstrate that T cell-dependent IgM memory B cells can be elicited at high frequency, and can play an important role in maintaining long-term immunity during bacterial infection.

The Majority of Human Memory B Cells Recognizing RhD and Tetanus Resides in IgM+ B Cells

“…Our findings in humans give support to the above-mentioned results obtained in mice (8,9,57), suggesting that IgM + memory represents a pool of long-lasting memory cells continuously replenishing the IgG + memory pool after repeated exposure. This may be beneficial upon second encounter with a mutated form of the original pathogen, triggering their ability to re-enter the GC, switch, and acquire additional mutations, resulting in higher affinity to the mutated Ag, as also suggested in an elegant murine study describing GC-independent unmutated IgG + memory B cells (58), which, similar to the IgM memory B cells characterized in this study, are implied to confer a great flexibility to the immune system by retaining germline sequences.…”

“…This discrepancy between the two murine studies may be related to the persistence of GC reactions in the response to particulate Ags: SRBCs in the study of Dogan et al (8), and soluble Ags in the study of Pape et al (9,56). It is relevant that we obtained similar results using a soluble Ag (TT) and a particulate Ag (D + RBCs), and that the kinetics of the memory subsets also resembled the observations of Pape et al More recently, another group studied the response to a TD Ag infection in mice and defined a subset of IgM memory B cells expressing CD11c, CD73, and PD-L2 (57). The absence of this IgM memory subset was found to abrogate the onset of IgG recall responses following a specific Ag challenge, thereby (again) supporting the idea that IgM memory plays an important role in maintaining long-term immunity.…”

Age-Associated B Cells: A T-bet–Dependent Effector with Roles in Protective and Pathogenic Immunity

“…These T-bet+ CD11c+ B cells appear at the peak of the humoral immune response during infection with mouse gammaherpesvirus 68, mouse cytomegalovirus, lymphocyte choriomeningitis virus, and vaccinia. B cells with very similar phenotypic and functional characteristics have also been recently described in Ehrlichia muris infection (37). Importantly, ABCs derived during these responses secrete virus-specific IgG upon restimulation in vitro more efficiently than FO B cells from the same host, indicating recruitment of antigen-specific B cells into the ABC pool, rather than nonspecific enlargement of a bystander ABC pool.…”

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…This altered humoral response in cGAS -/-mice was also reflected in lower levels of MSP1-specific IgG2C but not IgM (Figure 6, C and D). Expression of CD73, a marker associated with B cells that have interacted with T cells (51,52), was markedly reduced on both IgM + and IgM -memory B cells of cGAS -/-mice as compared with WT controls ( Figure 6E). We therefore concluded that ongoing infection is associated with poor GC function and memory B cell output in cGAS -/-mice.…”