What's the difference between naive and memory B cells?

What's the difference between naive and memory B cells?

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I understand that when naive B cells are exposed to antigens, they become memory B cells, but what is the functional difference between the two? I've looked at the quite a few article on B cells, but none of them stated the difference clearly enough for me to understand.

The main difference is that memory B cells start an immune reaction much more effective and faster than naive B cells. The reaction is also specific towards the antigen.

The memory B cell has a specific membrane receptor for an antigen. It produces specific antibodies only when exposed to the antigen.


  • Tangye SG, Avery DT, Deenick EK, Hodgkin PD. Intrinsic differences in the proliferation of naive and memory human B cells as a mechanism for enhanced secondary immune responses. J. Immunol. 2003 Jan 15;170(2):686-94. PubMed PMID: 12517929.

  • Wikipedia contributors, "B cell," Wikipedia, The Free Encyclopedia, (accessed June 26, 2014).

Naive B cells have not yet been trained by the immune system to recognize specific antigens -therefore the term "naive". Prior to antigen exposure, they must be trained in the bone marrow to recognize certain antigens.

Memory B cells, on the other hand, are formed after antigen exposure and clonal selection. As stated above, they have specific receptors for antigens and can produce antibodies.

Memory B cells

Germinal centre-independent memory B cells are generated from CD38 + GL7 + activated B cells. These memory B cells may maintain broad reactivity to the activating pathogen.

B1a and B1b cells can generate T cell-independent memory B cells.

IgG + and IgM + memory B cells have a distinct function. IgG + memory B cells preferentially differentiate into plasma cells, whereas IgM + memory B cells predominantly enter the germinal centre reaction.

Bona fide IgE + memory B cells are not present or, if they exist, they are present only as a small population.

Stimulation history, rather than the unique properties of the IgG cytoplasmic tail, is essential for exerting the rapid responses of IgG + memory B cells.

Memory T follicular helper cells support memory B cell responses. During this step, memory B cells are crucial antigen-presenting cells.

Phenotypic differences between naÏve and memory T CELLS

The supposition that naïve and memory T cells can be distinguished phenotypically is based on the notion that memory T cells retain a permanent imprint of having responded to antigen. Precise identification of memory T cells, however, remains problematic. Unlike B cells, T cells do not appear to mutate their antigen receptor genes during the course of an immune response. Furthermore, discrimination between effector and memory T cells is accomplished on the basis of rather nebulous criteria memory T cells are considered to differ from effector T cells by their continued survival after the acute immune response has died down and by being in a lower state of activation. As discussed further below, these distinctions are becoming increasingly blurred.

Despite these difficulties, a number of phenotypic differences between naïve and memory T cells have been noted. Most of these are changes that arise during initial T-cell activation and appear to persist in memory cells. Especially prominent are differences in the cell surface expression of adhesion molecules between naïve and memory T cells. Thus, compared to naïve T cells, memory T cells have been reported to express higher levels of β1 (CD29, CD49d and CD49e) and β2 (CD11a, CD11b and CD18) integrins, CD2, CD44, CD54 and CD58. 1-11 Increased expression of adhesion molecules on recently activated T cells reflects the requirements for effector T cells to enter peripheral tissues at sites of inflammation and interact with target cells, and may similarly affect the function of some memory T cells (see below).

The expression of other molecules involved in lymphocyte migration also differs between naïve and memory T cells. Of particular interest are differences in the expression of two key molecules required for the entry of T cells into lymph nodes through high endothelial venules (HEVs): CD62L and CCR7. CD62L binds to vascular addressins expressed on HEVs and is responsible for the initial stage of adherence of blood-borne T cells to HEVs, 12 while the CCR7 chemokine receptor controls responsiveness to chemokines expressed in HEVs at sites of lymphocyte entry. 13 Whereas naïve T cells are uniform in expressing high levels of both molecules, some memory cells lose expression of CD62L and/or CCR7. 14-17 However, memory T cells may express receptors for chemokines that direct them to inflammatory sites and for molecules involved in homing to peripheral tissues, such as the cutaneous lymphocyte antigen (CLA) which is involved in lymphocyte migration to skin. 17

Other cell surface molecules that have been reported to distinguish between naïve and memory T cells include the IL-2R β-chain (CD122), 18, 19 Ly-6C 19-21 and the common leukocyte antigen (CD45). 4, 6 14, 22-28 CD122 is a component of both the IL-2R and the IL-15R and may play a role in the maintenance of memory T cells (see below), 29 while Ly-6C is a low-molecular-weight (MW) glycosylphophatidylinositol-anchored molecule that has been proposed to participate in intercellular adhesion 30 both CD122 and Ly-6C are expressed at high levels on CD8 + memory T cells in the mouse. For CD45, which is a tyrosine phosphatase that regulates signalling through antigen receptors and cytokine receptors, 31, 32 it is the form of the molecule that differs between naïve and memory cells, rather than the level of expression. Multiple isoforms of CD45 are generated by differential splicing of three extracellular exons (A, B and C). These restricted (R) isoforms can be detected specifically with mAb directed against the variably spliced exons. Naïve T cells express the highest MW isoform, containing all three of these exons (commonly referred to as CD45RA in humans). During the course of T-cell activation, T cells switch to expressing lower-MW isoforms in humans at least, activated T cells express the isoform of CD45 lacking all three variably spliced exons (defined as CD45R0). In many different species, expression of low-MW isoforms of CD45 is retained on memory cells.

Since many of the phenotypic properties associated with memory T cells are in fact acquired soon after activation, these markers cannot be used on their own to discriminate between recently activated cells and memory cells. This distinction can be aided to a certain extent by combining these phenotypic markers with other criteria to exclude T cells that are actively responding to antigen. For example, it is generally assumed that memory T cells do not have a blasted morphology and do not express transient markers of activation such as CD69. Furthermore, differences in cell surface glycosylation have been reported to exist between effector and memory CD8 + T cells in mice. Specifically, memory cells have a higher degree of sialylation on 1 O-glycans and express lower levels of 2 O-glycans than effector cells 33-36 this difference can be detected using an antibody that binds specifically to CD43 only when this molecule has been modified by 2 O-glycans. 37 However, in using signs of recent activation as exclusion criteria for memory T cells, it must be borne in mind that even long-term memory cells appear to be more metabolically active than naïve T cells. 38 As discussed below, memory T cells undergo periodic rounds of cell division even in the complete absence of antigen. Therefore, markers of recent activation cannot be used definitively to distinguish between effector and memory T cells.

Although memory T cells are enriched amongst cells expressing the surface markers discussed above, it is also clear that memory cells exhibit substantial phenotypic heterogeneity. This issue has received considerable attention in recent years, with interest stemming largely from a report that CD45R0 + T cells in human blood can be divided into CD62L + CCR7 + and CD62L − CCR7 − subpopulations. 17 These cells have been termed ‘central memory’ and ‘effector memory’ cells, respectively, based on their expression of lymph node homing molecules and their functional properties (see below). In addition to CD62L and CCR7, memory T cells may express other markers associated with naïve T cells, such as high-MW isoforms of CD45. 16, 17 , 39-46

In some instances, it is evident that expression of a ‘naïve’ phenotype by primed cells represents phenotypic reversion. This has been shown to be the case for CD62L, CCR7 and high-MW isoforms of CD45, each of which can be re-expressed by cells that were formerly negative for these markers. 39, 41 , 47-52 Phenotypic reversion occurs at different rates in different species and also differs for CD4 vs. CD8 cells. For example, rat CD45RC − (memory-phenotype) CD4 + T cells re-express CD45RC within 1 week when transferred to secondary recipients in the absence of antigen 39, 41 the rapidity with which this reversion takes place suggests that the CD45RC – phenotype in the rat is a marker of recent activation rather than memory. Conversely, CD4 + memory T cells in mice can maintain a CD45RB low phenotype for at least 10 weeks in the absence of antigen, although CD8 + T cells re-express CD45RB soon after activation. 53

Phenotypic reversion is presumed to reflect a ‘cooling down’ of activated cells lack of contact with antigen results in a return to a resting state and the loss of expression of activation molecules. By corollary, retention of memory markers may be indicative of periodic contact with persisting antigen. However, some phenotypic markers, particularly the expression of high levels of CD44 on mouse memory T cells, appear to be retained long-term in the complete absence of antigen. 54, 55 In addition, mechanisms other than reversion may account for some of the phenotypic heterogeneity observed amongst memory T cells. In this respect, it is notable that some CD45RA + CD8 + T cells in human peripheral blood exhibit the properties of activated effector cells. 11 These cells, which also express low levels of CD28 and CD27, appear to arise from chronic antigenic stimulation. 56, 57 Likewise, some primed CD45RA + CD4 + T cells can be found under conditions of chronic antigen exposure. 45

Whether the CD45RA + cells observed in these studies have in fact re-expressed this molecule is unclear. Another possibility is that some cells may retain expression of CD45RA under certain conditions of activation. This is worth considering in view of data showing that mouse CD8 + T cells can differentiate directly into cells with the properties of central memory cells following antigenic stimulation in vitro. 58, 59 In these studies, brief exposure of CD8 + T cells to antigen followed by culture in IL-15 or low doses of IL-2 generated T cells that retained expression of CD62L and CCR7 and which lacked overt effector activity. By contrast, cells exposed to high concentrations of IL-2 after antigenic stimulation lost expression of CD62L and CCR7 and differentiated into effector cells. Therefore, acquisition of all of the markers typically associated with T-cell activation is not an inevitable consequence of antigenic stimulation.

Also complicating the use of phenotypic markers to distinguish between naïve and memory T cells is the fact that naïve T cells can acquire markers of memory cells in the absence of overt antigenic stimulation. This has been demonstrated to occur when small numbers of naïve cells are adoptively transferred into lymphopenic recipients. 60-68 Under these conditions, naïve T cells proliferate slowly (so-called homeostatic proliferation), up-regulate expression of activation/memory markers and exhibit effector activity. Notably, this response is driven not by specific antigen but by self-peptide-MHC complexes in combination with cytokines. 60, 61 , 64, 69-71 The contribution of cells generated by this process to the pool of memory-phenotype T cells in normal mice is unclear. However, the fact that very few memory-phenotype T cells are observed in germ-free mice argues that most memory-phenotype T cells are derived from antigenic stimulation. 27 Nevertheless, it remains possible that the phenotypic conversion associated with homeostatic proliferation may make a significant contribution to the pool of memory-phenotype T cells under conditions of lymphopenia.

Multiple Choice

Which of the following would be a T-dependent antigen?

A. lipopolysaccharide
B. glycolipid
C. protein
D. carbohydrate

Which of the following would be a BCR?

A. CD4
D. IgD

Which of the following does not occur during the lag period of the primary antibody response?

A. activation of helper T cells
B. class switching to IgG
C. presentation of antigen with MHC II
D. binding of antigen to BCRs

Primary and Secondary Immune Responses

The B and T-lymphocytes that are yet to encounter an antigen are called naive B and naive T-cells. The naive B-cells that encounter the antigen, proliferate and differentiate into two types of cells: the antibody-secreting plasma cells and the memory B-cells.

The plasma cells form the basis of primary immune response, which is the response mounted by the immune system to an antigen that the animal encounters for the first time. The primary response has a characteristic lag phase, during which naive B-cells proliferate and differentiate into plasma cells and memory cells.

Following this, serum antibody level increases logarithmically, reaches the peak at about day 14, remains at a plateaus for some time, then begins to drop off as the plasma cells begin to die. The memory cells remain in G0 phase, and have a much longer life than plasma cells some memory cells persist for the life of the individual.

Therefore, when the animal encounters the same antigen a second time, the population of memory cells responds rapidly to begin antibody secretion. The antibody levels peak in about 7 days, and the level of antibody is about 100 to 1,000-fold higher than that in the primary response.

The immune response mounted by the animal to an antigen, which it encounters a second time is called secondary immune response. The population of memory B-cells specific for a given antigen is considerably larger than the population of corresponding naive B-cells this accounts for some of the differences between primary and secondary immune responses (Fig. 41.4).

In a similar manner, the recognition of an antigen-MHC complex by a specific mature T-lymphocyte induces its proliferation and differentiation into TH cells and CTLs (the effector cells) and into memory cells.

The effector cells bring about the primary immune response, which is relatively slower it takes about 10-14 days in mouse for rejection of a skin graft in the first instance. But when skin tissue from the same source is grafted the second time, it is rejected in about 7-9 days due to the faster action of memory T-cells.

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E ffect of A ging on T C ell P henotypes

Natural aging has profound effects on many aspects of human physiology and is mainly thought to be associated with declining biological functions. However it is important to distinguish between healthy aging and pathological aging. The study of altered immune function in aging individuals can explain many different manifestations of the overall aging process, as well as the development of age-related life-threatening disorders including infections, cancers and atherosclerosis 49, 50 . Generally, the most striking age-related change observed in studies of the T cell compartment in aging individuals is an increase in the number of CD28- cells, as was predicted by the earlier in vitro studies of Effros and Walford 35 . Since CD28- T cells have been previously characterized as “senescent,” the T cells populations associated with aging were also been designated as senescent cells, eventually leading to the wider adoption of “immunosenescence” as a general biological concept. However, it is important to define key terms in order to better understand the sub-populations we assess when investigating senescence. Where “immunosenescence” describes age-related alterations at the immunological level (alternatively “immune erosion”), “immunological aging” refers instead to the apparent aging of individual immune cells and does not necessarily involve aged individuals or aging studies per se. While immunosenescence primarily refers to replicative senescence, the immunological aging process may include elements of both senescence and exhaustion. Against this backdrop, the initial concept that loss of CD28 was sufficient to identify “senescent” T cells was soon found to be unable to account for full extent of the age-associated changes widely observed in the CD4+ and CD8+ T cell compartments. Ongoing studies now indicate that accumulation of differentiated T cells, especially in the TEMRA subset, are hallmarks of aging.

These findings have had far reaching consequences for our understanding—and indeed misconceptions—of what constitutes immunosenescence. We now appreciate that impaired immune function in the elderly is likely a consequence of constant exposure to pathogens, some of which persist throughout life 50, 51 . This means that repeated pathogen encounter during chronological aging eventually exhausts the immune system, leading to the accumulation of highly differentiated T cells that are characterized by replicative senescence 7, 13, 33 . Clearly, this progressive loss of immune function with increasing age can have dramatic consequences for host protection, especially given that the thymus exhibits a concomitant loss of capacity to generate naïve T cells over time 52 . It has been nicely demonstrated that the naïve T cell pool in elderly humans is comprised of only 10% recent thymic emigrants and as much as 90% homeostatic naïve T cells, whereas in aged mice these proportions are exactly reversed 53 . The biological relevance of these findings can be summarized as follows (i) animal models provide only limited information on the maintenance of human immune homeostasis, (ii) aging is associated with a significant loss of thymic output, (iii) thymic involution may not be as detrimental as previously thought due to the broad antigen experience of elderly subjects, (iv) the imperative to maintain naïve T cell diversity may be a function of the prevailing environmental conditions of the host. The question therefore arises of whether these age-related changes necessarily mean a loss of function, or whether they represent a necessary adaptation to the host's surrounding environment?

This question is not easy to address because it is necessary to consider the functionality of the cells in question in combination with the immune reserve capacity (the status of the immune system that has been influenced by previous immunological history), the nature of the antigens involved, and the complex interactions between these factors. We must also consider the possible reversibility of the observed “impairment” of cellular functions, (as revealed by studies that have successfully blocked inhibitory receptors), and the fact CD28-T cells are not in fact committed to replicative senescence, because stimuli such as 4-1BBL, OX40L, IL-2, and IL-15 can promote the proliferation of these cells 23, 54 (although the response of CD28- T cells to IL-15 stimulation and their ability to undergo homeostatic proliferation appear somewhat heterogeneous) 23, 24, 55 . CD28-T cells produce variable quantities of pro-inflammatory cytokines that contribute to the state of low-grade inflammation known to be established during aging 56 . The intracellular signaling machinery of more differentiated memory CD4+ and CD8+ T cells is also known to display a persistent low-level of activation that alters the overall activation threshold of these cells 57 . The state of low-grade inflammation observed in elderly subjects is associated with low-level activation of cell signaling and is reflected by the distribution of T cell sub-populations. When maintained in this primed state, T cells can bypass the requirement for CD28 ligation in order to become activated. The long-term maintenance of this “ready-to-go” status in T cells exhausts the host's reserve of naïve cells, reduces clonal diversity, and leads to impaired functionality. However, from an evolutionary point of view, it may be more efficient to maintain a well-trained memory pool than to generate a new and diverse pool of naïve cells 58 . A concept that has now been largely removed from our current model of T cell differentiation, activation, senescence and exhaustion is the notion of “immunological reserves” that are maintained by cytokines such as IL-15 and IL-7 59 but undergo progressive depletion with aging. In our own laboratory, we have tested the possibility that expression of the IL-7 receptor (CD127) correlates with other markers of T cell history, namely CD28. In Figure 4 we show using a representative experiment that CD127 expression is maximal in CD28+ T cells and that CD28 mean fluorescence intensity (MFI) strongly correlates with CD127 MFI. This corroborates other studies demonstrating that naïve T cells are more responsive to IL-7 stimulation whereas memory cells are more responsive to IL-15. Technical issues complicate the study of IL-15R expression, but future investigation of the IL-7/IL-15 system in T cell sub-populations should clarify some of the key questions that arise from this discussion.

The immunological changes observed in aged individuals reflect the diversity and intensity of the antigenic challenges encountered during the host's lifespan. Among the many hypotheses proposed in order to explain immunosenescence in the elderly is the role of chronic viral infections, especially cytomegalovirus (CMV), for which accumulating evidence indicates a key role in driving exhaustion of T cells and induction of senescence.

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What is a Memory Cell? (with pictures)

In biology, a memory cell refers to one of a number of types of cells that make up part of the immune system. These cells are a vital part of the system that defends the body against pathogens such as bacteria or viruses that cause disease and infection. They are one type of white blood cell or lymphocyte. There are two main types, called memory T cells and memory B cells. T cells activate the immune system and directly attack pathogens, while B cells produce substances called antibodies, which can disable or kill pathogens.

A memory cell starts its life in the bone marrow, where lymphocytes are made. It is then transported around the body in lymph, a clear liquid that, among other functions, transports lymphocytes to regions of infection. Lymph is transported around the body via the lymphatic system, a network of vessels and tissues throughout the body.

The function of these cells is characterized by the memory present in acquired immunity. Once a memory cell, either a T cell or a B cell, has been exposed to a specific pathogen, it will react much more rapidly when it encounters the same pathogen in the future. This is the reason that some diseases can normally only be caught once by a person. If a person suffers from an infection such as measles, these cells "learn" how to get rid of the virus that causes the disease. Once the measles virus has been successfully fought off once, then any future infections with measles viruses will normally be repulsed without the person becoming ill.

Another example of how such cells work in the immune system includes vaccination. A vaccine actually contains the pathogen that causes the disease that the vaccine is designed to prevent. The pathogen is either weakened or dead so that it is not usually strong enough to make the recipient of the vaccine ill. In its weakened form, it still stimulates the immune system, allowing the B and T cells to "learn" how to fight off that specific pathogen. In the future, if the person is exposed to the pathogen in its virulent form, he or she is much more likely to be able to recover from the infection quickly, either not becoming ill or only suffering a mild version of the disease.

This work was supported by grants from the NIH (D.K.N., P.J.N., M.J.R.) and an American Society for Hematology Bridge Award (M.J.R.). D.S. is a member of the Medical Scientist Training Program at MCW, which is partially supported by a training grant from NIGMS T32-GM080202. This work benefitted from data assembled by the ImmGen consortium. 42

The authors declare no competing financial interests.

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.


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