Human peripheral blood age‐associated (CD11c+Tbet+) B cells: No association with age

Based on the well-established observation that aged individuals develop impaired antibody responses to neo-antigens in general, and especially to vaccines, making this age group more susceptible to infectious challenges [1], many groups have focused on the study of the B cell subpopulations that could underly this cohort's humoral deficiency. These studies brought to light age-associated B cell (ABC) phenotypes bearing a putative relation with the declining B cell function. However, different markers and labels describing these atypical subpopulations have been used. Actually, these cells were named ABCs because they were first described in elderly mice, and characterized phenotypically by low CD21 expression, expression of CD11c, and detectable levels of CD95 [2, 3]. A recently published proposal for comprehensive phenotyping of human B cells reports on a small subset of unusual memory B cells lacking CD27, CD21, and CD38 expression, already present in healthy individuals but which would increase with age [4]. These authors argue that others have also described these unusual B cells as ageassociated B cells (ABC), atypical memory B cells, tissue-based memory cells, double negative (DN)/late memory B cells, CD11c+ B cells, or memory Tbet+ B cells. However, it is unclear whether they all refer to the same subset, mainly because alternative phenotype markers have been used (e.g., IgD, CD10, CD11c, Blimp, among others). B cells are not a uniform population, they diverge according to their differential pathway, which relates to a variety of phenomena such as the strength and length of engagement with their antigen receptors, the presence of other stimuli, and others [5]. Age associated B cell were first described in mice, in which our knowledge progressed significantly while in humans it has been hampered by issues such as different phenotypic definitions for the ABC population, diverse combinations of surface and intracellular markers and names. Although there are several classifications of B cells, the most common classification starts with the division of B cells into four subpopulations using IgD and CD27 expression: Naive (IgD+CD27 ), Switched (IgD CD27+), Unswitched (IgD+CD27+), and Double negative (IgD CD27 ). In general DN cells are pointed as age associated B cells, but according to recent reviews [4, 6, 7], these cells comprise more phenotypes than the ABCs, since not all DN are necessarily CD21 , CD11c+ and TbeT+. ABC has recently been the subject of more in-depth reviews, especially those cells bearing the CD11c+Tbet+ phenotype [8–10]. These cells can be found in the blood, spleen, and bone marrow, but rarely in lymph nodes [5, 11]. Because of low levels of CXCR5 and CCR7 expression they are not located in lymph nodes [5]. Despite the heterogeneity of phenotype markers, these B cells share certain features, suggesting that they are expanded in various settings of chronic immune activation, a feature also associated with aging. They would represent a population of functionally exhausted B cells based on their significant replication history, accumulation of somatic hypermutations, and poor ex vivo responses to activation [12, 13]. However, the issue of whether these cells increase with and their role in immunosenescence remains inconclusive [8–10]. Gil Benard and Juliana Ruiz Fernandes share senior authorship. Received: 21 March 2023 Revised: 23 May 2023 Accepted: 9 June 2023