Innate immunity, the first line of defense against infectious pathogens and cancer cells, relies on a variety of cell types to carry out its pathogen-fighting and clean-up functions. Resident cells present in most tissues serve as sentinels, detect danger signals and send for help. Phagocytic cells—such as macrophages and neutrophils—respond to the call, infiltrate the injured tissue and, along with a variety of immunological mediators, initiate the inflammatory response. In addition, innate lymphocytes, which include natural killer cells and the so-called innate lymphoid cells, serve both as effectors and regulators during the innate immune response. The major effector functions of innate lymphocytes include direct cytotoxicity and secretion of cytokines.
Innate lymphoid cells have only relatively recently been discovered in humans. They differ from the B and T lymphocytes of the adaptive immune response—innate lymphoid cells lack antigen-specific receptors and respond very rapidly once the presence of pathogens is detected by the sentinel cells. Thus, they play a critical role in defending the body’s barrier regions such as skin, lungs, and gut.
There are three subgroups of innate lymphoid cells, which differ from each other on the basis of their response to signaling molecules and secretion of cytokines. Similarly to the natural killer (NK) cells, one of these subgroups—called group I innate lymphoid cells (ILC1s)—produces large amounts of the cytokine interferon γ (IFN-γ), and activate innate and adaptive immunity.
Now, results from a study (Natural killer-like B cell prime innate lymphocytes against microbial infection) published in the journal Immunity identifies a previously unknown lymphocyte subpopulation. This lymphocyte population expresses the B cell lineage marker CD19, along with the NK markers NK1.1 and Nkp46, and has been called natural killer-like B (NKB) by the study authors.
NKB cells are present in humans and in all commonly used inbred mouse strains, differ from T and B cells, express a fully rearranged BCR, and produce the cytokines interleukin-18 (IL-18) and interleukin-12 (IL-12) soon after infection. Through the action of these cytokines, NKB cells rapidly activate NK cells and ILC1 cells, thus playing a major role in the elimination of pathogens by priming immune responses against infectious pathogens, in particular intracellular pathogens. Indeed, activation of NK cells and ILC1 cells by NKB cells leads to production of IFN-γ, which is essential to the early control of a variety of viral and intracellular bacterial infections. As expected on the basis of their regulatory role, NKB cells are rapid responders—they proliferate within 24 hr after intracellular bacterial infections, whereas NK and ILC1 cell expansion peaks around day 3 in the same experimental system.
Thus, the study unveils an important new innate-like lymphoid cell subset that regulates activation of NK cells and ILC1 cells and participates in the generation of adaptive immune responses.
As NKB cells play an active role in the activation of NK cells and ILC1 cells, what would happen if a person has a mutation with NKB? In other words, would the body completely be defenseless or is there another way to activate the innate and adaptive immunity without NKB cells?
From what I learned, the NKB cells not only activates the NK cells, but also play important roles in inhibition of microbial infection at the beginning. The organisms which don’t have NKBs will be more susceptible to L. monocytogenes and S. typhimurium infection, and the lack of NKBs will make bacteria set more easily in spleen and MLNs. Therefore, organisms with the mutation of NKBs will have more serious tissue damage caused by L. monocytogenes.
In my opinion, the body without NKBs won’t be defenseless because there are other ways to activate innate and adaptive immunity, and I don’t think the presence of NKBs is the main source to stimulate the immune response. For example, NKBs activate natural killer cells by secreting IL-18 cytokines. However, IL-18 can also be secreted by macrophages. Therefore, I think NKBs mutation won’t cause a significant damage to the immunity, but lack of NKBs will also cause abnormal conditions.
Wang, S., Xia, P., Chen, Y., Ye, B., Du, Y., & Fan, Z. (2016, July 19). Natural Killer-like B cells Prime Innate Lymphocytes against Microbial Infection. Immunity, 45, 131-144.
This is an interesting question for the further investigations.
Natural killer-like B (NKB) cells are sub population of lymphocytes which are found in the spleen and mesenteric lymph node. NKB express the B cell marker CD19 and IgM as well as NK cell marker NK1.1 and NKp46 but lacks other lineage markers such as CD3, CD4, CD8, CD11b, CD11c, Gr1, F4/80, and Ter119. NKB has the unique feature that makes them different from B cell and NK cells. Secretion of cytokines (such as IFN-g and tumor necrosis factor-alpha, TNF-alpha) and direct killing are the two major effector responses of NK cells (Fan et al., 2005; Sun and Lanier, 2011). However, NKBs neither produced IFN-gamma nor exhibited cytotoxicity. B cells are characterized by secretion of antibodies under lipopolysaccharides (LPS) challenge. However, NKBs failed to generate IgM upon LPS stimulation. It differs from T and B cell is that it produces IL-12 and IL-18 at an early stage of infection. In the study carried out by Wang et al, 2016. they emphasize the NKB cells as the part of innate immune system. Regarding the adaptive immune system, NKB induces the immune response independently of T or B cell. Till date we do not have any evidences or study carried out regarding the effect of NKB mutation on immunity, but on the basis of above description revealed by the study of S.W et al aid to assume that the mutation on NKB cell might affect the innate immunity but might not have significant effect on adaptive immunity as NKB cell trigger the immune response independent of T and B cell. Nevertheless, the impacts of NKB mutation on immune system still need further investigation.
Fan Z, Yu P, Wang Y, Wang Yu, Fu ML, Liu W, Sun Y, Fu YX. NK-cell activation by LIGHT triggers tumor-specific CD8+ T- cell immunity to reject established tumors. Blood 2005-08-3485.
Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8+ T cells. Nature Reviews Immunology 2011 Aug 26;11(10):645-57
This is my first time to hear about NKB cells, and NKB cells are really interesting because NKBs are kind of between B cells and NK cells. They have genes that express B cell receptors and also have NK cell characteristic Ly49 genes. The difference between NKBs and B cells is that NKBs don’t produce IgM as a response to LPS stimulation. And the big difference between NK cells and NKB cells is that NKB cells neither secrete cytokines, such as IFN- or kill infected cells directly. Instead, IL-18 and IL-12 are the major cytokines that NKBs generated. NKBs are very important and can response to pathogens very quickly.
I also found another interesting cells called natural killer T cells (NKTs). Just like NKBs, NKTs are sharing properties with T cells and NK cells. What attracts me is that NKTs can recognize glycolipids presented by CD1d molecules, instead of MHC molecules, this is a big difference between NKTs and T cells. Unlike NKBs, NKTs can secrete IFN-. I know that NKBs play a critical role in innate immune response at early stage, and the NKTs play a role in the level of cytokines in human, and in my opinion, NKTs don’t express a very special function. However, NKTs cannot be depleted because lacking of NKTs can cause diabetes, or some cancers. I am still confused about the reason.
Wang, S., Xia, P., Chen, Y., Ye, B., Du, Y., & Fan, Z. (2016, July 19). Natural Killer-like B cells Prime Innate Lymphocytes against Microbial Infection. Immunity, 45, 131-144.
I am wondering if NKB cells are necessary for immune system function. It seems their role in innate immunity is to secrete cytokines to activate the NK cells. We know already though that NK cells are activated by type 1 interferons secrete by plasmacytoid dendritic cells, and are further activated by macrophages during infection. So are NKB cells also a necessary part of the process of activating NK cells? Is there some kind of regulation for all these activators of NK cells? I would imagine that over activation of the NK cells might lead to autoimmune type reactions.
I also wish this post would have covered the other subsets of innate lymphoid cells as well. Through my research, I learned of a subset of innate lymphocytes called lymphoid tissue inducer cells. Though not much is known about these cells, they have been found to be prominent during fetal development, and contribute to the development of further lymphoid tissues. They express Interleukin 22, which initiates the innate immune response.
Innate lymphoid cells differ from adapting lymphocytes in that they are not antigen specific. What else separates innate and adaptive lymphocytes? And what determines proliferation of B and T lymphocytes, versus innate lymphocytes such as NKB cells or lymphoid tissue inducer cells. It seems that the discovery of innate lymphocytes is fairly recent, and more research needs to be done on them.
The innate immunity is something everyone is familiar with, including how it works and the cells involved. Now there is something new in the mix called an NKB cell. Since this cell is seen to express both B cell lineage markers and NK cell markers, it would seem to be some type of NK cell/B cell hybrid. It is written in the article that these NKB cells are the ones that activate NK cells during the innate immunity response. Does this mean that after macrophages and monocytes play their role in the beginning of the innate response, that NKB cells are the sole cells to thank for inducing your NK cells to start defending you? Not exactly, when the macrophages and the monocytes can’t attack on their own anymore they do call upon NK cells for help, but the NKB cells may do a little more work than we have ever given them credit for until now. The one point that makes me raise an eyebrow is when they say it has a B cell lineage marker, CD19, since B cells are involved in adaptive immunity and these NKB cells are written about in a way of innate lymphocyte cells, does that mean that some adaptive immunity characteristics are crossed over in these NKB cells? Is the innate immune response and the adaptive immune response slightly more intertwined than we think?
In response to the question you postulated, if NKB cells were discovered to contain CD19+ B cell linage marker is this indicative of the development of enhanced ability of Natural killer (NK) cells in adaptive immunity? Prior to the discovery of NKB cells, NK cells were characterized as lacking the cell marker CD19 after maturation and differentiation from CD34+ progenitor cells mature and differentiated based. One of the challenges of conducting in depth experimental research of NK cells is the fact that mainly murine and in-vitro models have been that differ from human NK cells such as the inability of CD56 expression by mice, which plays a role in cytokine production as well immunoregulatoion regulation of other NK cells in the secondary lymphoid tissues. It should also be stated that typically CD56+ NK cells circulate in small amounts in the peripheral blood system and their presence in the secondary lymphoid tissues is heavily influenced by the microenvironment of NK progenitor cells.
The recent discovery of various subsets of NK cells with different cell surface molecules and gene expression influencing the producing of different cytokines and cytotoxic ability eludes to the fact that NK cells may have more functions and subclasses, such as the NKB cells, capable of functioning in the adaptive immune system that have yet to be discovered. I am curious about whether NKB cells have always existed and now due to advances in modern technology the relative small percentage of NKB cells can be studied via immunological scientific experimentation. Perhaps another causative factor that led to the discovery of NKB cells relates to a CD19 gene mutation in NK progenitor cells with gene expression resulting in mature, differentiated NKB cells containing the cell surface CD19 marker, with improved innate and adaptive response that ultimately led to their continued clonal selection & clonal expansion?
Freud AG, Yokohama A, Becknell B, et al. Evidence for discrete stages of human natural killer cell differentiation in vivo. The Journal of Experimental Medicine. 2006;203(4):1033-1043. doi:10.1084/jem.20052507.
You made a great point in trying to use the possible origins of the NKB cell to decipher its true functions. Due to the lack of information on the NKB cells I feel it is important to conceptualize the NKB cell’s origin to extrapolate the information need to answer the questions we all have. For us to be able to understand the cells we would have to view it from a genetic standpoint. During an infection – whether it be from a virus, bacterial agent, or helminth – it is important to remember that if an organism cannot effectively deal with the antigen before the load becomes too high then this leads to the demise of the organism. Therefore, there would be certain genetic rearrangements that would allow the organism to survive or in this case the evolution of a cell that could integrate functions of both the innate and adaptive immune responses. Due the the presence of BCR on the surface of the NKB cells such as IGM, which is a non-specific receptor it has potential to bind a large amount of varying antigen types, and the ability to release pro-inflammatory cytokines, the NKB cells can be seen as a cell that is used to start the innate immune response. In my opinion the NKB cells is to the innate immune response as the dendritic cells are to the adaptive immune response.
These NKB cells are intriguing as they express B cell markers as well as NK markers. Their role in the innate immune response as rapid responders makes sense and got me thinking about their possible role in the adaptive immune response. Upon reading the original study I found that the crosstalk revealed between adaptive and innate lymphocytes have many implications which are unknown at this time. Will we be able to exploit NKB cells and use them to our benefit in the adaptive as well as innate immune system? The study briefly mentions that IL-18 is an inflammatory factor which promotes autoimmune disease. Could the discovery of NKB cells get us closer to solving the problem of overreactive or misguided immune response of the body to itself? I am interested to see what future research reveals about the specific role of NKB cells in autoimmune response. This may be a key component in the puzzle of autoimmune disease response.
Though I found the discovering of natural killer-like B cell (NKB) fascinating, it begs the question how does NKB distinguish between self and non-self. Why is NKB producing lots of interleukin-18 in both the initial and post infection and those it means that NKB is only present during chronic inflammation? Why do NKB cells exhibited high amounts of Pax5 (B cell transcription factor) but only expresses low amounts of DNA-binding protein inhibitor (NK cell transcription factor)? Being that the study mentioned that NKB has B cell lineage marker and CD19 those it means that NKB also play a vital role in adaptive immune response too?
Puncture wounds, such as cuts and minor abrasions, allow pathogens to break the impermeable skin layer causing the possibility of infections. Once the pathogens rupture the mucosal surfaces under the skin, the innate immune system will initiate a response. This inherited defense system allows for fast acting, non-specific reactions occurring in two steps. The first phase involves the recognition of the pathogen by cell- surface receptors and binding proteins. Destructive effector cells make up the second response in which the pathogen is destructed. Swelling and inflammation are typically signs of the localized innate immune reaction. Frequently, the innate immunity is enough to kill the infective germs. The adaptive immune system is activated when the pathogen is not successfully eliminated through the initial response. White blood cells, known as lymphocytes, are the powerhouses of the long-lasting adaptive immunity. More specific targets for particularly challenging pathogens are generated during this response. Although the adaptive immunity is slower to act, it can memorize particular pathogen activity if the body were to be exposed to the same germ another time. The antibody, secreted by fully differentiated B cells called plasma cells, is a key factor for the adaptive immunological reaction. Dozens of antibodies can be created for highly specialized defense. Furthermore, T cells, both cytotoxic T cells and helper T cells, are crucial for the aiding or killing pathogens.
Now with this new research, scientists have suggested that the immune system can be manipulated for effective drug therapies. Natural killer like B cells (NKB) may have the potential to produce antibacterial effects. This discovery is definitely fascinating. As suggested in a prior study, there are treatments involving IFN-γ that have proven successful against certain microbial infections, more specifically the Burkholderia pseudomallei infection. It would be interesting to see if the same Macrophage infection assays and in vivo pulmonary challenge models used in this study could be used to prove the effectiveness of NKB.
Propst, K. L., Troyer, R. M., Kellihan, L. M., Schweizer, H. P., & Dow, S. W. (2010). Immunotherapy Markedly Increases the Effectiveness of Antimicrobial Therapy for Treatment of Burkholderia pseudomallei Infection. Antimicrobial Agents and Chemotherapy, 54(5), 1785-1792. doi:10.1128/aac.01513-09
I too was fascinated with this new study. Just like many previous posts as this new player NKB cells was new to me as well. It showed these hybrid innate cells, which express both NK and B cell markers. The one item that really stood out to me within this study was NKB cells did not secrete antibody after stimulation. If NKB are involved in early production IL-18, then how does this affect with IgM functions? IgM is the first antibody produced when an infection has never been exposed to that particular infection. How does NKB cells exposure to infection modify the immune system? How does it evolve? I looked forward for further research for NKB cells in the innate immune response.
This is a very interesting finding. NKBs must be extremely potent and their effects must be short lasting if they only expand within a 24 hour period and eventually subside which makes sense since their job is to trigger ILCs in order to prime the immune response to deal with pathogens. Though NKBs have not been shown to lead to autoimmune disorders, they may be the answer to fixing them. By figuring how to regulate NKBs and their production of IL-18 and IL-12 we may be able to reduce the inflammation leading to the problems caused by autoimmune disorders like rheumatoid arthritis. Since NKBs lead to the activation of several other factors like NK cells, TNF-gamma, by understanding each and their possible contribution to autoimmune disorders and being able to control their levels so they are defeating the pathogen but not being overproduced, maybe this can reduce the outcome of someone getting an autoimmune disorder.