Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • Log out
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • ASN Publications
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • Log out
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • JASN Podcasts
    • Article Collections
    • Archives
    • Kidney Week Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Editorial Fellowship
    • Editorial Fellowship Team
    • Editorial Fellowship Application Process
  • More
    • About JASN
    • Advertising
    • Alerts
    • Feedback
    • Impact Factor
    • Reprints
    • Subscriptions
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
UP FRONT MATTERSBrief Reviews
You have accessRestricted Access

Recently Discovered T Cell Subsets Cannot Keep Their Commitments

Terry B. Strom and Maria Koulmanda
JASN August 2009, 20 (8) 1677-1680; DOI: https://doi.org/10.1681/ASN.2008101027
Terry B. Strom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Maria Koulmanda
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

After activation by antigen/MHC (signal 1) and CD28-dependent co-stimulation (signal 2), resting CD4+ T cells commit to one of a variety of functionally and molecularly defined phenotypes. Two long established CD4 phenotypes, Th1 and Th2 cells, have been regarded as terminally differentiated formats. Recently, two additional phenotypes, tissue-protective regulatory (Tregs) and tissue-destructive Th17 T cells, have also been discovered, and neither represents a terminally differentiated phenotype. Rather, Tregs and Th17+ cells respond to cues provided by the inflammatory texture in which these cells reside. We review the important scientific and therapeutic implications of these differences herein.

Naive CD4+ T cells are activated after interaction of T cell receptors with antigen/MHC (signal 1) and co-stimulation (signal 2). Depending on the fine texture of the inflammatory milieu in which antigen activation takes place, these newly activated T cells commit to one of several CD4+ subset phenotypes (Figure 1). In addition to the classical Th1 and Th2 CD4+ phenotypes, regulatory (Treg) and Th17 phenotypes have been more recently identified and characterized. Whereas effector T cells such as the Th1, Th2, and Th17 phenotypes exert injurious, cytopathic effects on tissues, the Treg phenotype restrains or “regulates” effector T cell–mediated tissue injury.

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

The clinical outcome, rejection or tolerance, of the allograft response is determined by the relative balance between rejection-causing cytopathic T-bet+ Th1 and RORγt+ Th17 CD4+ T cells versus rejection blocking, cytoprotective FOXP3+ Tregs.

Paradigm Lost

Naive CD4+ cells T commit to the tissue-destructive, γ-IFN–expressing Th1 program when signals 1 and 2 are delivered in a milieu rich in IL-12, a product of certain stimulated antigen-presenting cells.1 In contrast, antigen activation conducted in an IL-4–rich environment leads to commitment to the Th2 phenotype1 (Figure 1). Commitment to the Th1 or Th2 phenotype rests with expression of a distinctive DNA-binding lineage specification factor by CD4+ T cells (Figure 1). Expression of the t-bet specification factor commits newly antigen-activated and IL-12–stimulated CD4+ T cells to the Th1 phenotype. In contrast, expression of GATA 3 commits newly antigen-activated and IL-4–stimulated T cells to the Th2 phenotype.1 Until recently, it was thought, upon antigen activation, helper T cells became either Th1 or Th2 T cells.2

IL-2–producing Th1 and IL-4–producing Th2 are considered terminally differentiated phenotypes; that is, once they commit, there is no “going back.” Th1 and Th2 cells were once held responsible for diametrically opposing functions in tissue injury. Th1 cells were the most potent mediator and principle architects of CD4-dependent tissue-destructive reactions, whereas Th2 cells were thought to protect antigen-bearing tissues from Th1 cells. This paradigm was supported by data first coming from the work of Mosmann and colleagues3 and subsequently supported by numerous laboratories showing a prominent Th1 and less potent Th2 response in rejecting allografts harvested from untreated hosts or in tissue undergoing T cell–dependent autoimmune injury. In tissues obtained from tolerant hosts, a diametrically opposing scenario in which a prominent Th2 and diminutive Th1 response is manifest. Although this scenario is easy to remember, Th1 cells attack while Th2 cells protect “foreign” tissues, it is not altogether true. Th1 cells, γ-IFN4 or IL-2 (Th1 cell products) are not required for rejection.5 Indeed, anti–IL-12 treatment, used to neutralize the Th1-promoting effects of IL-12, does—as expected—dramatically ablate the antidonor Th1 response and enhance the antidonor Th2 response, but rejection of MHC-mismatched tissues is not delayed. In short, rejection of MHC-mismatched allografts can be conducted by T cells in the Th2 mode.6

Tregs and Immune Tolerance

CD4+ Tregs, not Th2 cells, are crucially important in restraining the destructive effects of cytopathic T cells (Figure 2). In keeping with new dogma that CD4+ T cells take cues from the cytokine environment, a TGF-β–dominant environment leads naive CD4+ T cells to commit to the regulatory phenotype.7 Indeed, this commitment is obtained by the TGF-β–triggered expression of the lineage-unique Foxp3 lineage specification factor.8,9 Whereas newly antigen-activated and TGF-β–stimulated, mature, naive CD4+ T cells are induced to express the Treg phenotype, a population of Foxp3+ “natural” Tregs also emerge from the thymus with potent regulatory properties.7 Hence, two populations, induced and natural Tregs, exist. Unfortunately, a single convenient cell surface marker that discriminates induced from natural Tregs has not been found, thereby creating considerable difficulty in establishing the individual roles of induced and natural Tregs in the induction and maintenance of tolerance.

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

After activation with antigen and co-stimulation, naive CD4+ T cells commit to one of several molecular and functional phenotypes. This commitment is governed by the cytokine content of the microenvironment in which antigen activation transpires. In the presence of IL-12, IL-4, or TGF-β, T cells commit to Th1, Th2, or Tregs, whereas the presence of both TGF-β and IL-6 in mice or IL-1β, IL-6, or TNF-α in humans fosters commitment to the Th17 phenotype. Each subset expresses a lineage specification factor, such as T-bet, and expresses a distinctive panel of cytokines.

Humans born with loss-of-function or deletional mutations of Foxp3 rapidly develop devastating forms of autoimmunity.7 In mice, a similar situation pertains, and destruction of Foxp3 T cells in adult mice also leads to prominent autoimmunity. There can be no doubt that Foxp3+ Tregs are crucial to the development and maintenance of tolerance, although a role for other immunoregulatory cells is not precluded. In fact, other regulatory cells are well characterized,10 although their precise role in immune tolerance is less certain. The means by which Tregs restrain effector T cells from destroying antigen-bearing tissue seems multifactorial and includes cell–cell interactions with both effector T cells and dendritic cells as well as release of immunosuppressive cytokines, such as TGF-β and IL-10, and the generation of adenosine catalyzed by subset-specific expression of ectoenzymes.8,9,11 Indeed, synchronized expression of the CD39 and CD73 enzymes that coordinately catalyze the generation of adenosine may be the most precise cell surface signature for mouse Tregs.11

Th17 Cells: A New Potent Effector T Cell Population

Remarkably, TGF-β, in the presence of IL-612 or IL-212, promotes commitment of naive murine and human CD4+ T cells to the highly cytopathic Th17 phenotype (Figure 1). In humans, other proinflammatory cytokines, including TNF-α and IL-1β in addition to IL-6, elicit a similar effect.13 Indeed, the presence of these proinflammatory cytokines precludes commitment of naive CD4+ T cells to the regulatory phenotype.2,12,14,15 Regulation of the commitment of naive CD4+ T cells to the Th17 phenotype is governed by unique lineage specification factors within the retinoic acid receptor–related orphan nuclear receptor family.16 In this case, two specification factors, RORγt and to a lesser extent RORα, co-conspire to direct commitment to the Th17 phenotype. Th17 cells express a variety of potent proinflammatory cytokines including but not limited to IL-17A, IL-17F, and osteopontin. IL-23, although not necessary for the commitment to the Th17 phenotype, is essential to stabilize this commitment.17 Th17 cells are potent effector cells, perhaps more potent than Th1 cells, in several but not all autoimmune states.14 A vicious cycle in respect to Th17-dependent tissue destruction is formed through the ability of Th17 cells to stimulate antigen-presenting cells to express IL-6 and by the ability of IL-6 to stimulate commitment of naive T cells to the Th17 phenotype.

Th17 cells participate in extremely inflamed forms of T cell–dependent tissue injury. Within these toxic environments, the ability of Foxp3+ T cells to restrain effector T cells from executing tissue injury is severely compromised.2,14 Owing to the violence of Th17-dependent tissue injury, a means to target Th17 selectively for therapy is a potentially important unmet need. The precise role of Th17 cells in rejection is under study by our and other laboratories. Preliminary experiments suggest, as is the case in autoimmune diseases, that Th17 cells participate in rejection.

Can T Cells Keep Their Commitments?

The pivotal role of particular cytokines in dictating the precise nature of the commitments of naive T cells undergoing antigen activation is now clear for the Th17 as well as for the Treg, Th1, and Th2 phenotypes (Figure 1). Thus, the role of cytokines in directing differentiation or commitment to the Th17 and Treg phenotypes is new but also classical in the sense that cytokines are widely known to influence the expression of lineage-determining specification-type transcription factors.

Unprecedented is the recent discovery that the cytokine and inflammatory milieu in which Tregs and Th17 cell function alters the molecular and functional phenotype of these committed, presumably terminally differentiated T cells. For example, IL-2715 stimulates Th17 cells to express IL-10, an immunosuppressive cytokine, and thereby negates the ability of these cells to act as tissue-destructive effector cells.18 Moreover, Th17 cells require IL-23 to expand and maintain viability.19,20 Thus, maintenance of the Th17 viability of the tissue-injuring effector phenotype is not immutable, because Th17 cells take all important cues from the state of innate immunity in the microenvironment in which they reside. In a parallel manner, stimulation of Foxp3+ regulatory T cells with an agonist type anti–T cell Ig mucin domain 1 mAb triggers loss of immunoregulatory function and downregulation of Foxp3 and TGF-β by Tregs.21

In short, a detailed knowledge of the molecular and functional phenotype of previously unknown T cell subsets has emerged from recent work. Moreover, the fine texture of inflammation within the milieu of antigen-driven CD4+ T cell responses in triggering commitment to and destabilization from tissue-destructive and tissue-protective CD4 subset phenotypes shapes the intensity of CD4-dependent immunity. This new information suggests shortcomings in many time-honored strategies to gain T cell tolerance and new strategies to achieve this elusive goal in transplant recipients and patients with autoimmune diseases.

Immunologists, with good reason, have directly targeted T cells in attempts to subdue autoimmunity and allograft rejection or stimulate cancer immunity. Although these strategies are well founded and have spurred major advances in treatment, the opportunity to use parallel strategies to modify the state of innate immunity in which T cell activation or re-activation has not received equal attention. The road untaken may be laden with opportunity. For example, we tested the hypothesis that inflammatory mechanisms directly trigger the loss of immune tolerance to islets and β cell–destructive insulitis in the NOD mouse. Treatment with α1 antitrypsin, an agent that dampens inflammation but does not inhibit T cell activation directly, ablates invasive insulitis and restores euglycemia, immune tolerance to β cells, normal insulin signaling, and insulin responsiveness in NOD mice with recent-onset type 1 diabetes by favorable changes in the inflammation milieu.22 Indeed, the functional mass of β cells expands in α1 antitrypsin–treated diabetic NOD mice.

Disclosures

None.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • Copyright © 2009 by the American Society of Nephrology

References

  1. 1.↵
    1. O'Garra A,
    2. Arai N
    : The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol 10: 542–550, 2000
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Korn T,
    2. Bettelli E,
    3. Gao W,
    4. Awasthi A,
    5. Jäger A,
    6. Strom TB,
    7. Oukka M,
    8. Kuchroo VK
    : IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448: 484–487, 2007
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Fiorentino DF,
    2. Bond MW,
    3. Mosmann TR
    : Two types of mouse T helper cell: IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170: 2081–2095, 1989
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Konieczny BT,
    2. Dai Z,
    3. Elwood ET,
    4. Saleem S,
    5. Linsley PS,
    6. Baddoura FK,
    7. Larsen CP,
    8. Pearson TC,
    9. Lakkis FG
    : IFN-gamma is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways. J Immunol 160: 2059–2064, 1998
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Steiger J,
    2. Nickerson PW,
    3. Steurer W,
    4. Moscovitch-Lopatin M,
    5. Strom TB
    : IL-2 knockout recipient mice reject islet cell allografts. J Immunol 155: 489–498, 1995
    OpenUrlAbstract
  6. 6.↵
    1. Li XC,
    2. Zand MS,
    3. Li Y,
    4. Zheng XX,
    5. Strom TB
    : On histocompatibility barriers, Th1 to Th2 immune deviation, and the nature of the allograft responses. J Immunol 161: 2241–2247, 1998
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Sakaguchi S,
    2. Yamaguchi T,
    3. Nomura T,
    4. Ono M
    : Regulatory T cells and immune tolerance. Cell 133: 775–787, 2008
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Tang Q,
    2. Bluestone JA
    : The Foxp3+ regulatory T cell: A jack of all trades, master of regulation. Nat Immunol 9: 239–244, 2008
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Fontenot JD,
    2. Gavin MA,
    3. Rudensky AY
    : Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol 4: 330–336, 2003
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Allan SE,
    2. Broady R,
    3. Gregori S,
    4. Himmel ME,
    5. Locke N,
    6. Roncarolo MG,
    7. Bacchetta R,
    8. Levings MK
    : CD4+ T-regulatory cells: toward therapy for human diseases. Immunol Rev 223: 391–421, 2008
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Deaglio S,
    2. Dwyer KM,
    3. Gao W,
    4. Friedman D,
    5. Usheva A,
    6. Erat A,
    7. Chen JF,
    8. Enjyoji K,
    9. Linden J,
    10. Oukka M,
    11. Kuchroo VK,
    12. Strom TB,
    13. Robson SC
    : Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204: 1257–1265, 2007
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Bettelli E,
    2. Carrier Y,
    3. Gao W,
    4. Korn T,
    5. Strom TB,
    6. Oukka M,
    7. Weiner HL,
    8. Kuchroo VK
    : Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441: 235–238, 2006
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Acosta-Rodriguez EV,
    2. Napolitani G,
    3. Lanzavecchia A,
    4. Sallusto F
    : Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8: 942–949, 2007
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Korn T,
    2. Oukka M,
    3. Kuchroo V,
    4. Bettelli E
    : Th17 cells: Effector T cells with inflammatory properties. Semin Immunol 19: 362–371, 2007
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Awasthi A,
    2. Carrier Y,
    3. Peron JP,
    4. Bettelli E,
    5. Kamanaka M,
    6. Flavell RA,
    7. Kuchroo VK,
    8. Oukka M,
    9. Weiner HL
    : A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 8: 1380–1389, 2007
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Manel N,
    2. Unutmaz D,
    3. Littman DR
    : The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 9: 641–649, 2008
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Dong C
    : Diversification of T-helper-cell lineages: Finding the family root of IL-17-producing cells. Nat Rev Immunol 6: 329–333, 2006
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Stumhofer JS,
    2. Silver JS,
    3. Laurence A,
    4. Porrett PM,
    5. Harris TH,
    6. Turka LA,
    7. Ernst M,
    8. Saris CJ,
    9. O'Shea JJ,
    10. Hunter CA
    : Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 8: 1363–1371, 2007
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Zhou L,
    2. Ivanov II.,
    3. Spolski R,
    4. Min R,
    5. Shenderov K,
    6. Egawa T,
    7. Levy DE,
    8. Leonard WJ,
    9. Littman DR
    : IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8: 967–974, 2007
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Volpe E,
    2. Servant N,
    3. Zollinger R,
    4. Bogiatzi SI,
    5. Hupé P,
    6. Barillot E,
    7. Soumelis V
    : A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 9: 650–657, 2008
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Degauque N,
    2. Mariat C,
    3. Kenny J,
    4. Zhang D,
    5. Gao W,
    6. Vu MD,
    7. Alexopoulos S,
    8. Oukka M,
    9. Umetsu DT,
    10. DeKruyff RH,
    11. Kuchroo V,
    12. Zheng XX,
    13. Strom TB
    : Immunostimulatory Tim-1-specific antibody deprograms Tregs and prevents transplant tolerance in mice. J Clin Invest 118: 735–741, 2008
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Koulmanda M,
    2. Bhasin M,
    3. Hoffman L,
    4. Fan Z,
    5. Qipo A,
    6. Shi H,
    7. Bonner-Weir S,
    8. Putheti P,
    9. Degauque N,
    10. Libermann TA,
    11. Auchincloss H Jr.,
    12. Flier JS,
    13. Strom TB
    : Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci USA 105: 16242–16247, 2008
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 20 (8)
Journal of the American Society of Nephrology
Vol. 20, Issue 8
1 Aug 2009
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Recently Discovered T Cell Subsets Cannot Keep Their Commitments
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Recently Discovered T Cell Subsets Cannot Keep Their Commitments
Terry B. Strom, Maria Koulmanda
JASN Aug 2009, 20 (8) 1677-1680; DOI: 10.1681/ASN.2008101027

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Recently Discovered T Cell Subsets Cannot Keep Their Commitments
Terry B. Strom, Maria Koulmanda
JASN Aug 2009, 20 (8) 1677-1680; DOI: 10.1681/ASN.2008101027
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Paradigm Lost
    • Tregs and Immune Tolerance
    • Th17 Cells: A New Potent Effector T Cell Population
    • Can T Cells Keep Their Commitments?
    • Disclosures
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

UP FRONT MATTERS

  • Molecular Characterization of Membranous Nephropathy: Quo Vadis?
  • More than a Marker: Arginase-1 in Kidney Repair
  • Enabling Patient Choice: The “Deciding Not to Decide” Option for Older Adults Facing Dialysis Decisions
Show more UP FRONT MATTERS

Brief Reviews

  • Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach
  • Salt-Losing Tubulopathies in Children: What’s New, What’s Controversial?
  • Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives
Show more Brief Reviews

Cited By...

  • A Novel Role for Type 1 Angiotensin Receptors on T Lymphocytes to Limit Target Organ Damage in Hypertension
  • Basic and Translational Concepts of Immune-Mediated Glomerular Diseases
  • Chemokines in Renal Injury
  • The Emergence of Th17 Cells as Effectors of Renal Injury
  • TIM-3: A Novel Regulatory Molecule of Alloimmune Activation
  • Endothelial-Regenerating Cells: An Expanding Universe
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe to ASN Journals

© 2022 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire