- Email: [email protected]
It’s Hard to Teach an Old B Cell New Tricks
Leading Edge
Previews It’s Hard to Teach an Old B Cell New Tricks Jenna J. Guthmiller1 and Patrick C. Wilson1,* 1Department of Medicine, Section of Rheumatology, the Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cell.2019.12.019
Victora and colleagues challenge current perceptions that memory B cells readily participate in secondary germinal center reactions, allowing further modification of specificity upon reactivation. Rather, naı¨ve B cells are the predominant B cell type that populate secondary germinal centers. This work has important basic immunological and translational implications.
B cells adapt the specificity and affinity of antibodies by somatic hypermutation and competition, causing accelerated evolution of the immunoglobulin variable region genes, collectively referred to as affinity maturation. During primary antigenic exposure, naive B cells undergo affinity maturation within a germinal center (GC) and emerge as antibodysecreting plasma cells (PCs) and memory B cells (MBCs). MBCs are critical first responders upon secondary exposures, producing high-affinity antibodies. Additionally, it has typically been assumed that MBCs can readily reenter the GC to undergo further affinity maturation to produce higher-affinity clones or to retune specificity to rapidly evolving pathogens such as HIV or influenza. The latter concept is being exploited in efforts to produce vaccines to such evolving pathogens that are refractory to vaccination due to immune escape. However, little is known about the B cell composition and clonal relationships to the primary GC response of secondary GCs. Using a prime-boost immunization model, in this issue of Cell, Mesin and Schiepers et al. tracked primary GCderived MBCs and found that secondary GC responses predominantly derive from naive B cells rather than pre-existing MBCs (Mesin et al., 2020). The primary B cell clonal landscape is large and diverse, resulting in a wide array of MBC clones generated. However, the MBCs recalled into secondary GC responses are restricted to only a few clones that also constitute a significant proportion of the antibody-secreting B cell populations (Figure 1). Thus, this study highlights that the reentrance of MBCs to GCs is a
rare event involving only particular B cell clones. Previous studies have largely employed the adoptive transfer of MBCs to naive animals, and they have revealed that discrete populations of MBCs are primed to reenter GCs to undergo further affinity maturation. The MBCs recruited into secondary GCs are largely classswitched and harbor a higher number of somatic hypermutations, consistent with a previous study using hapten immunization (McHeyzer-Williams et al., 2015). Although not directly explored in this article, MBCs that can reenter GCs may demonstrate features of previously described MBC subsets recruited into secondary GCs, including higher somatic mutation loads as observed or a less mature phenotype (Krishnamurty et al., 2016; Zuccarino-Catania et al., 2014). The authors report that the predicted germline, or unmutated (naive-precursor) version of antibody genes from GC-recalled MBCs, encodes antibodies with higher affinity for antigen than those from MBCs that did not reenter GCs. These data suggest that high-affinity naive B cell clones used during a primary response become licensed to preferentially participate in immune memory and GC responses upon future antigen exposures (Figure 1). It is also possible that over extended periods of time, MBCs that were not activated for secondary immune responses may eventually become competent for GC reentry. It is yet to be seen whether longer-lived species such as humans may have increased capacity to reactivate and retrain MBCs. Either model or other unappreciated mechanisms suggest that
18 Cell 180, January 9, 2020 ª 2019 Elsevier Inc.
there are distinct MBC subsets, of which only some have license to reenter GCs. This study highlights the role of naive B cell recruitment and de novo affinity maturation in GCs upon secondary exposure. Rather than continued affinity maturation of MBCs against a few epitopes, clonally diverse naive B cells are recruited to respond upon secondary exposure. This finding likely has implications for immunity against pathogens such as influenza viruses and Plasmodium falciparum, which are commonly attributed to the accumulation of antibodies against multiple variable epitopes of hemagglutinin and PfEMP1, respectively (Tessema et al., 2019), and a continued need to adapt to new antigenic variants. Because the GC is a competitive environment, it stands to reason that existing high-affinity MBCs should have limited input into GCs as these clones would already express high-affinity immunoglobulins, out-competing and limiting adaptation to new or diverse epitopes. Thus, to pathogens that are antigenically stable, only new additional antibodies or improved high-affinity antibodies will result, driving improved protection with each boost. Finally, as naive B cell production declines with age, the prevalence of naive B cells in recalled GC responses may explain the lack of efficient B cell adaption after influenza vaccination in the elderly (Henry et al., 2019). Consistent with these findings, MBCs may be refractory to continued affinity maturation even after multiple antigenic exposures, particularly in the case of influenza. Although this article did not assess how secondary GCs altered the landscape of MBC clones upon tertiary
Figure 1. Reentry of Only Rare MBCs into Germinal Centers Naive B cells (BN) are recruited into the germinal center (GC) response upon primary exposure and undergo affinity maturation and selection and ultimately become memory B cells (MBCs) or antibody-secreting plasma cells (PCs). Upon secondary exposure to hemagglutinin (HA), the GC becomes primarily composed of newly recruited naive B cells and the MBCs with the strongest affinity. Cells depicted in yellow were derived from naive precursors with higheraffinity B cell receptors. Those in green were from cells with lower-affinity B cell receptors. TFH, T follicular helper cell, orange cells; FDC, follicular dendritic cell, blue cells; DZ, dark zone; LZ, light zone.
exposure, naive B cells likely continue to contribute upon re-exposure. The continued recruitment of a select set of MBC clones may be the basis of B cell immunodominance and phenomena such as imprinting and original antigenic sin (Victora and Wilson, 2015). Repeated vaccination may continue to recall only particular MBCs, leading to oligoclonality against pathogens, as observed in humans against influenza viruses (Andrews et al., 2015; Lee et al., 2019). Oligoclonality against protective epitopes will lead to continued affinity maturation and boosting of protective antibodies. Conversely, against non-protective epitopes, oligoclonality may lead to susceptibility to infection or severe disease. For mutagenic viruses such as influenza or HIV, immune selective pressure will preferentially select viruses that have mutated protective epitopes so that the few ‘‘licensed’’ MBCs that remain will tend not to be protective. This line of reasoning suggests that, for chronic or repeated immune activation against mutagenic pathogens, protective epitopes will be targeted in a biased fashion by de novo-activated naive B cells that are lower affinity and that continued affinity maturation of high-affinity MBCs will be against less protective epitopes, or original antigenic sin. Moreover, the pref-
erential usage of only a few MBC clones may also explain why the occurrence of broadly neutralizing antibodies against HIV is so rare, requiring years and multiple rounds of affinity maturation (Wu et al., 2015). Together, this phenomenon would limit the induction of broadly neutralizing antibodies against antigenically diverse pathogens. In conclusion, to the majority of pathogens that express relatively invariant and globally conserved epitopes, focused memory responses would only improve upon re-exposure. However, memory may hinder protection to antigenically diverse pathogens. This finding has important translational implications as it suggests that preferred epitopes to be targeted by vaccines, i.e., broadly conserved epitopes on HIV or influenza, should be directly accessible by the naive B cell repertoire. Therefore, immunogens that preferentially induce antibodies against immunosubdominant epitopes and induce higher-affinity germline antibodies may be necessary to overcome these hurdles. ACKNOWLEDGMENTS Work on understanding B cell immune responses and particularly influenza in the Wilson lab is funded by the National Institute of Allergy and Infectious Disease (NIAID) Collaborative
Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051 (P.C.W.); NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract (P.C.W.: HHSN272201400005C); and NIAID grants U19AI082724 (P.C.W.), U19AI109946 (P.C.W.), and U19AI057266 (P.C.W.).
REFERENCES Andrews, S.F., Huang, Y., Kaur, K., Popova, L.I., Ho, I.Y., Pauli, N.T., Henry Dunand, C.J., Taylor, W.M., Lim, S., Huang, M., et al. (2015). Immune history profoundly affects broadly protective B cell responses to influenza. Sci. Transl. Med. 7, 316ra192. Henry, C., Zheng, N.Y., Huang, M., Cabanov, A., Rojas, K.T., Kaur, K., Andrews, S.F., Palm, A.E., Chen, Y.Q., Li, Y., et al. (2019). Influenza Virus Vaccination Elicits Poorly Adapted B Cell Responses in Elderly Individuals. Cell Host Microbe 25, 357–366.e6. Krishnamurty, A.T., Thouvenel, C.D., Portugal, S., Keitany, G.J., Kim, K.S., Holder, A., Crompton, P.D., Rawlings, D.J., and Pepper, M. (2016). Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge. Immunity 45, 402–414. Lee, J., Paparoditis, P., Horton, A.P., Fruhwirth, A., McDaniel, J.R., Jung, J., Boutz, D.R., Hussein, D.A., Tanno, Y., Pappas, L., et al. (2019). Persistent Antibody Clonotypes Dominate the Serum Response to Influenza over Multiple Years and Repeated Vaccinations. Cell Host Microbe 25, 367–376.e5.
Cell 180, January 9, 2020 19
McHeyzer-Williams, L.J., Milpied, P.J., Okitsu, S.L., and McHeyzer-Williams, M.G. (2015). Classswitched memory B cells remodel BCRs within secondary germinal centers. Nat. Immunol. 16, 296–305. Mesin, L., Schiepers, A., Ersching, J., Barbulescu, A., Cavazzoni, C.B., Angelini, A., Okada, T., Kurosaki, T., and Victora, G.D. (2020). Restricted Clonality and Limited Germinal Center Reentry Characterize Memory B Cell Reactivation by Boosting. Cell 180, this issue, 92–106.
Tessema, S.K., Nakajima, R., Jasinskas, A., Monk, S.L., Lekieffre, L., Lin, E., Kiniboro, B., Proietti, C., Siba, P., Felgner, P.L., et al. (2019). Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants. Cell Host Microbe 26, 579–590.e5. Victora, G.D., and Wilson, P.C. (2015). Germinal center selection and the antibody response to influenza. Cell 163, 545–548. Wu, X., Zhang, Z., Schramm, C.A., Joyce, M.G., Kwon, Y.D., Zhou, T., Sheng, Z., Zhang, B.,
O’Dell, S., McKee, K., et al.; NISC Comparative Sequencing Program (2015). Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell 161, 470–485. Zuccarino-Catania, G.V., Sadanand, S., Weisel, F.J., Tomayko, M.M., Meng, H., Kleinstein, S.H., Good-Jacobson, K.L., and Shlomchik, M.J. (2014). CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat. Immunol. 15, 631–637.
May the (Mechanical) Force Be with AT2 Julio Sainz de Aja1,2,3 and Carla F. Kim1,2,3,* 1Stem Cell Program, Division of Hematology/Oncology and Division of Respiratory Disease, Boston Children’s Hospital, Boston, MA 02115, USA 2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA 3Harvard Stem Cell Institute, Cambridge, MA 02138, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cell.2019.12.020
Idiopathic pulmonary fibrosis is a fatal disease involving destruction of the lung alveolar structure. In this issue of Cell, Wu et al. (2020) show that impaired alveolar (AT2) stem cells produce mechanical tension that leads to spatially regulated fibrosis, initiating a new chapter in understanding what underlies the periphery to center progression of this lung disease. A long time ago in a lung far, far away . so goes the limited understanding of how idiopathic pulmonary fibrosis (IPF) develops; very little is understood of the early stages or the progression of this deadly disease. Fibrosis involves an over-proliferation of fibroblasts and the accumulation of extracellular matrix. In the lung, the most common type of fibrosis is idiopathic pulmonary fibrosis. Clinical studies have documented that this disease starts in the periphery and progresses toward the center of the lung (Figure 1) (Plantier et al., 2011), yet why this occurs is unknown. The concept of mechanical tension as a driver of IPF has been previously contemplated but never formally proven in a fibrotic progression context (Zhang et al., 2015). It is known that IPF affects alveolar type II (AT2) cells, the stem cells of the lung’s alveolar units. However, the mechanisms by which AT2 cells contribute to IPF path-
ogenesis are still unknown. In this issue of Cell, Wu et al. (2020) now link the mechanical tension caused by lung fibrosis to impaired alveolar stem cells. Elevated mechanical tension caused by defective alveolar stem cells generates an activation loop of TGFß signaling that is more substantial in the lung periphery and eventually extends toward the central part of the lung, explaining a long-standing question about IPF. The findings bridge an important new link between stem cell defects and fibrosis and while doing so provide new ways to model the disease. For the first time, their paper shows that a differentiation defect in lung alveolar stem cells (AT2 cells) stimulates fibrosis progression. Previously, Tang and colleagues connected Cdc42, a member of the RhoGTPase family, with alveolar regeneration—a connection that implies stem cell involvement (Liu et al., 2016). Wu
20 Cell 180, January 9, 2020 ª 2019 Elsevier Inc.
et al. (2020) show that in mice with Cdc42-null AT2 cells, there is no new generation of alveolar type I cells, the pneumocytes that perform gas exchange. Thus, Cdc42-null AT2 cells have a differentiation defect. As a consequence, mice lacking Cdc42 in AT2 cells after injury or with aging develop a progressive fibrosis. Because the disease in these mice does not resolve and more closely resembles the spatial-temporal aspects of human disease progression, this could be a better way to model fibrosis than the widely used bleomyocin injury. Interestingly, Cdc42 could also provide a connection to another cellular process linked to IPF. Previous studies have shown accelerated epithelial senescence plays a role in IPF pathogenesis (Minagawa et al., 2011), and Cdc42 is involved in senescence (Wang et al., 2007). Indeed, the concept
Previews It’s Hard to Teach an Old B Cell New Tricks Jenna J. Guthmiller1 and Patrick C. Wilson1,* 1Department of Medicine, Section of Rheumatology, the Knapp Center for Lupus and Immunology, University of Chicago, Chicago, IL 60637, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cell.2019.12.019
Victora and colleagues challenge current perceptions that memory B cells readily participate in secondary germinal center reactions, allowing further modification of specificity upon reactivation. Rather, naı¨ve B cells are the predominant B cell type that populate secondary germinal centers. This work has important basic immunological and translational implications.
B cells adapt the specificity and affinity of antibodies by somatic hypermutation and competition, causing accelerated evolution of the immunoglobulin variable region genes, collectively referred to as affinity maturation. During primary antigenic exposure, naive B cells undergo affinity maturation within a germinal center (GC) and emerge as antibodysecreting plasma cells (PCs) and memory B cells (MBCs). MBCs are critical first responders upon secondary exposures, producing high-affinity antibodies. Additionally, it has typically been assumed that MBCs can readily reenter the GC to undergo further affinity maturation to produce higher-affinity clones or to retune specificity to rapidly evolving pathogens such as HIV or influenza. The latter concept is being exploited in efforts to produce vaccines to such evolving pathogens that are refractory to vaccination due to immune escape. However, little is known about the B cell composition and clonal relationships to the primary GC response of secondary GCs. Using a prime-boost immunization model, in this issue of Cell, Mesin and Schiepers et al. tracked primary GCderived MBCs and found that secondary GC responses predominantly derive from naive B cells rather than pre-existing MBCs (Mesin et al., 2020). The primary B cell clonal landscape is large and diverse, resulting in a wide array of MBC clones generated. However, the MBCs recalled into secondary GC responses are restricted to only a few clones that also constitute a significant proportion of the antibody-secreting B cell populations (Figure 1). Thus, this study highlights that the reentrance of MBCs to GCs is a
rare event involving only particular B cell clones. Previous studies have largely employed the adoptive transfer of MBCs to naive animals, and they have revealed that discrete populations of MBCs are primed to reenter GCs to undergo further affinity maturation. The MBCs recruited into secondary GCs are largely classswitched and harbor a higher number of somatic hypermutations, consistent with a previous study using hapten immunization (McHeyzer-Williams et al., 2015). Although not directly explored in this article, MBCs that can reenter GCs may demonstrate features of previously described MBC subsets recruited into secondary GCs, including higher somatic mutation loads as observed or a less mature phenotype (Krishnamurty et al., 2016; Zuccarino-Catania et al., 2014). The authors report that the predicted germline, or unmutated (naive-precursor) version of antibody genes from GC-recalled MBCs, encodes antibodies with higher affinity for antigen than those from MBCs that did not reenter GCs. These data suggest that high-affinity naive B cell clones used during a primary response become licensed to preferentially participate in immune memory and GC responses upon future antigen exposures (Figure 1). It is also possible that over extended periods of time, MBCs that were not activated for secondary immune responses may eventually become competent for GC reentry. It is yet to be seen whether longer-lived species such as humans may have increased capacity to reactivate and retrain MBCs. Either model or other unappreciated mechanisms suggest that
18 Cell 180, January 9, 2020 ª 2019 Elsevier Inc.
there are distinct MBC subsets, of which only some have license to reenter GCs. This study highlights the role of naive B cell recruitment and de novo affinity maturation in GCs upon secondary exposure. Rather than continued affinity maturation of MBCs against a few epitopes, clonally diverse naive B cells are recruited to respond upon secondary exposure. This finding likely has implications for immunity against pathogens such as influenza viruses and Plasmodium falciparum, which are commonly attributed to the accumulation of antibodies against multiple variable epitopes of hemagglutinin and PfEMP1, respectively (Tessema et al., 2019), and a continued need to adapt to new antigenic variants. Because the GC is a competitive environment, it stands to reason that existing high-affinity MBCs should have limited input into GCs as these clones would already express high-affinity immunoglobulins, out-competing and limiting adaptation to new or diverse epitopes. Thus, to pathogens that are antigenically stable, only new additional antibodies or improved high-affinity antibodies will result, driving improved protection with each boost. Finally, as naive B cell production declines with age, the prevalence of naive B cells in recalled GC responses may explain the lack of efficient B cell adaption after influenza vaccination in the elderly (Henry et al., 2019). Consistent with these findings, MBCs may be refractory to continued affinity maturation even after multiple antigenic exposures, particularly in the case of influenza. Although this article did not assess how secondary GCs altered the landscape of MBC clones upon tertiary
Figure 1. Reentry of Only Rare MBCs into Germinal Centers Naive B cells (BN) are recruited into the germinal center (GC) response upon primary exposure and undergo affinity maturation and selection and ultimately become memory B cells (MBCs) or antibody-secreting plasma cells (PCs). Upon secondary exposure to hemagglutinin (HA), the GC becomes primarily composed of newly recruited naive B cells and the MBCs with the strongest affinity. Cells depicted in yellow were derived from naive precursors with higheraffinity B cell receptors. Those in green were from cells with lower-affinity B cell receptors. TFH, T follicular helper cell, orange cells; FDC, follicular dendritic cell, blue cells; DZ, dark zone; LZ, light zone.
exposure, naive B cells likely continue to contribute upon re-exposure. The continued recruitment of a select set of MBC clones may be the basis of B cell immunodominance and phenomena such as imprinting and original antigenic sin (Victora and Wilson, 2015). Repeated vaccination may continue to recall only particular MBCs, leading to oligoclonality against pathogens, as observed in humans against influenza viruses (Andrews et al., 2015; Lee et al., 2019). Oligoclonality against protective epitopes will lead to continued affinity maturation and boosting of protective antibodies. Conversely, against non-protective epitopes, oligoclonality may lead to susceptibility to infection or severe disease. For mutagenic viruses such as influenza or HIV, immune selective pressure will preferentially select viruses that have mutated protective epitopes so that the few ‘‘licensed’’ MBCs that remain will tend not to be protective. This line of reasoning suggests that, for chronic or repeated immune activation against mutagenic pathogens, protective epitopes will be targeted in a biased fashion by de novo-activated naive B cells that are lower affinity and that continued affinity maturation of high-affinity MBCs will be against less protective epitopes, or original antigenic sin. Moreover, the pref-
erential usage of only a few MBC clones may also explain why the occurrence of broadly neutralizing antibodies against HIV is so rare, requiring years and multiple rounds of affinity maturation (Wu et al., 2015). Together, this phenomenon would limit the induction of broadly neutralizing antibodies against antigenically diverse pathogens. In conclusion, to the majority of pathogens that express relatively invariant and globally conserved epitopes, focused memory responses would only improve upon re-exposure. However, memory may hinder protection to antigenically diverse pathogens. This finding has important translational implications as it suggests that preferred epitopes to be targeted by vaccines, i.e., broadly conserved epitopes on HIV or influenza, should be directly accessible by the naive B cell repertoire. Therefore, immunogens that preferentially induce antibodies against immunosubdominant epitopes and induce higher-affinity germline antibodies may be necessary to overcome these hurdles. ACKNOWLEDGMENTS Work on understanding B cell immune responses and particularly influenza in the Wilson lab is funded by the National Institute of Allergy and Infectious Disease (NIAID) Collaborative
Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051 (P.C.W.); NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract (P.C.W.: HHSN272201400005C); and NIAID grants U19AI082724 (P.C.W.), U19AI109946 (P.C.W.), and U19AI057266 (P.C.W.).
REFERENCES Andrews, S.F., Huang, Y., Kaur, K., Popova, L.I., Ho, I.Y., Pauli, N.T., Henry Dunand, C.J., Taylor, W.M., Lim, S., Huang, M., et al. (2015). Immune history profoundly affects broadly protective B cell responses to influenza. Sci. Transl. Med. 7, 316ra192. Henry, C., Zheng, N.Y., Huang, M., Cabanov, A., Rojas, K.T., Kaur, K., Andrews, S.F., Palm, A.E., Chen, Y.Q., Li, Y., et al. (2019). Influenza Virus Vaccination Elicits Poorly Adapted B Cell Responses in Elderly Individuals. Cell Host Microbe 25, 357–366.e6. Krishnamurty, A.T., Thouvenel, C.D., Portugal, S., Keitany, G.J., Kim, K.S., Holder, A., Crompton, P.D., Rawlings, D.J., and Pepper, M. (2016). Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge. Immunity 45, 402–414. Lee, J., Paparoditis, P., Horton, A.P., Fruhwirth, A., McDaniel, J.R., Jung, J., Boutz, D.R., Hussein, D.A., Tanno, Y., Pappas, L., et al. (2019). Persistent Antibody Clonotypes Dominate the Serum Response to Influenza over Multiple Years and Repeated Vaccinations. Cell Host Microbe 25, 367–376.e5.
Cell 180, January 9, 2020 19
McHeyzer-Williams, L.J., Milpied, P.J., Okitsu, S.L., and McHeyzer-Williams, M.G. (2015). Classswitched memory B cells remodel BCRs within secondary germinal centers. Nat. Immunol. 16, 296–305. Mesin, L., Schiepers, A., Ersching, J., Barbulescu, A., Cavazzoni, C.B., Angelini, A., Okada, T., Kurosaki, T., and Victora, G.D. (2020). Restricted Clonality and Limited Germinal Center Reentry Characterize Memory B Cell Reactivation by Boosting. Cell 180, this issue, 92–106.
Tessema, S.K., Nakajima, R., Jasinskas, A., Monk, S.L., Lekieffre, L., Lin, E., Kiniboro, B., Proietti, C., Siba, P., Felgner, P.L., et al. (2019). Protective Immunity against Severe Malaria in Children Is Associated with a Limited Repertoire of Antibodies to Conserved PfEMP1 Variants. Cell Host Microbe 26, 579–590.e5. Victora, G.D., and Wilson, P.C. (2015). Germinal center selection and the antibody response to influenza. Cell 163, 545–548. Wu, X., Zhang, Z., Schramm, C.A., Joyce, M.G., Kwon, Y.D., Zhou, T., Sheng, Z., Zhang, B.,
O’Dell, S., McKee, K., et al.; NISC Comparative Sequencing Program (2015). Maturation and Diversity of the VRC01-Antibody Lineage over 15 Years of Chronic HIV-1 Infection. Cell 161, 470–485. Zuccarino-Catania, G.V., Sadanand, S., Weisel, F.J., Tomayko, M.M., Meng, H., Kleinstein, S.H., Good-Jacobson, K.L., and Shlomchik, M.J. (2014). CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat. Immunol. 15, 631–637.
May the (Mechanical) Force Be with AT2 Julio Sainz de Aja1,2,3 and Carla F. Kim1,2,3,* 1Stem Cell Program, Division of Hematology/Oncology and Division of Respiratory Disease, Boston Children’s Hospital, Boston, MA 02115, USA 2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA 3Harvard Stem Cell Institute, Cambridge, MA 02138, USA *Correspondence: [email protected] https://doi.org/10.1016/j.cell.2019.12.020
Idiopathic pulmonary fibrosis is a fatal disease involving destruction of the lung alveolar structure. In this issue of Cell, Wu et al. (2020) show that impaired alveolar (AT2) stem cells produce mechanical tension that leads to spatially regulated fibrosis, initiating a new chapter in understanding what underlies the periphery to center progression of this lung disease. A long time ago in a lung far, far away . so goes the limited understanding of how idiopathic pulmonary fibrosis (IPF) develops; very little is understood of the early stages or the progression of this deadly disease. Fibrosis involves an over-proliferation of fibroblasts and the accumulation of extracellular matrix. In the lung, the most common type of fibrosis is idiopathic pulmonary fibrosis. Clinical studies have documented that this disease starts in the periphery and progresses toward the center of the lung (Figure 1) (Plantier et al., 2011), yet why this occurs is unknown. The concept of mechanical tension as a driver of IPF has been previously contemplated but never formally proven in a fibrotic progression context (Zhang et al., 2015). It is known that IPF affects alveolar type II (AT2) cells, the stem cells of the lung’s alveolar units. However, the mechanisms by which AT2 cells contribute to IPF path-
ogenesis are still unknown. In this issue of Cell, Wu et al. (2020) now link the mechanical tension caused by lung fibrosis to impaired alveolar stem cells. Elevated mechanical tension caused by defective alveolar stem cells generates an activation loop of TGFß signaling that is more substantial in the lung periphery and eventually extends toward the central part of the lung, explaining a long-standing question about IPF. The findings bridge an important new link between stem cell defects and fibrosis and while doing so provide new ways to model the disease. For the first time, their paper shows that a differentiation defect in lung alveolar stem cells (AT2 cells) stimulates fibrosis progression. Previously, Tang and colleagues connected Cdc42, a member of the RhoGTPase family, with alveolar regeneration—a connection that implies stem cell involvement (Liu et al., 2016). Wu
20 Cell 180, January 9, 2020 ª 2019 Elsevier Inc.
et al. (2020) show that in mice with Cdc42-null AT2 cells, there is no new generation of alveolar type I cells, the pneumocytes that perform gas exchange. Thus, Cdc42-null AT2 cells have a differentiation defect. As a consequence, mice lacking Cdc42 in AT2 cells after injury or with aging develop a progressive fibrosis. Because the disease in these mice does not resolve and more closely resembles the spatial-temporal aspects of human disease progression, this could be a better way to model fibrosis than the widely used bleomyocin injury. Interestingly, Cdc42 could also provide a connection to another cellular process linked to IPF. Previous studies have shown accelerated epithelial senescence plays a role in IPF pathogenesis (Minagawa et al., 2011), and Cdc42 is involved in senescence (Wang et al., 2007). Indeed, the concept