Skip to main content
SpringerLink
Log in

Formation of B and T cell subsets require the cannabinoid receptor CB2

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

A recent and surprising body of research has linked changes in immune function to biologic and therapeutic targeting of cannabinoid receptors, which prototypically respond to delta-9 tetrahydrocannabinol. The peripheral cannabinoid receptor CB2 is highly expressed in immune cell types (macrophages, dendritic cells, and B cells), and pharmacologically alters their cytokine production and responsiveness. Accordingly, cannabinoid agonists can powerfully alter susceptibility to certain microbial infections, atherosclerosis, and cancer immunotherapy. What is unknown is the physiologic role of natural levels of endocannabinoids and their receptors in normal immune homeostasis. Gαi2−/− mice are deficient in the formation of certain B and T cell subsets and are susceptible to immune dysregulation, notably developing inflammatory bowel disease. A key issue is the identity of the Gi-coupled receptors relevant to this Gαi2-signaling pathway. We find that mice deficient in CB2, the Gi-coupled peripheral endocannabinoid receptor, have profound deficiencies in splenic marginal zone, peritoneal B1a cells, splenic memory CD4+ T cells, and intestinal natural killer cells and natural killer T cells. These findings partially phenocopy and extend the lymphocyte developmental disorder associated with the Gαi2−/− genotype, and suggest that the endocannabinoid system is required for the formation of T and B cell subsets involved in immune homeostasis. This noncompensatable requirement for physiologic function of the endocannabinoid system is novel. Because levels of endocannabinoids are highly restricted microanatomically, local regulation of their production and receptor expression offers a new principle for regional immune homeostasis and disease susceptibility, and extends and refines the rationale for CB2-targeted immunotherapy in immune and inflammatory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

αGalCer/CD1:

Murine CD1d tetramer loaded with α-galactosylceramide

BAFF:

B cell-activating factor belonging to the TNF family receptor

BAFF-R:

BAFF receptor

DTT:

Dithiothreitol

GCPR:

G-coupled protein receptor

IEL:

Intraepithelial lymphocytes

LI:

Large intestine

MLN:

Mesenteric lymph node

MZ:

Marginal zone B cells

PC:

Peritoneal cell

SI:

Small intestine

T1:

Transitional type-1 B cell

T2:

Transitional type-2 B cell

References

  • Bendelac A, Bonneville M, Kearney JF (2001) Autoreactivity by design: innate B and T lymphocytes. Nat Rev Immunol 1:177–186

    Article  PubMed  CAS  Google Scholar 

  • Bilsborough J, Viney JL (2004) In vivo enhancement of dendritic cell function. Ann N Y Acad Sci 1029:83–87

    Article  PubMed  CAS  Google Scholar 

  • Blumberg RS, Saubermann LJ, Strober W (1999) Animal models of mucosal inflammation and their relation to human inflammatory bowel disease. Curr Opin Immunol 11:648–656

    Article  PubMed  CAS  Google Scholar 

  • Borm ME, He J, Kelsall B, Pena AS, Strober W, Bouma G (2005) A major quantitative trait locus on mouse chromosome 3 is involved in disease susceptibility in different colitis models. Gastroenterology 128:74–85

    Article  PubMed  CAS  Google Scholar 

  • Borowski C, Bendelac A (2005) Signaling for NKT cell development: the SAP-FynT connection. J Exp Med 201:833–836

    Article  PubMed  CAS  Google Scholar 

  • Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, Le Fur G, Casellas P (1993) Cannabinoid-receptor expression in human leukocytes. Eur J Biochem 214:173–180

    Article  PubMed  CAS  Google Scholar 

  • Bouaboula M, Poinot-Chazel C, Marchand J, Canat X, Bourrie B, Rinaldi-Carmona M, Calandra B, Le Fur G, Casellas P (1996) Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. Eur J Biochem 237:704–711

    Article  PubMed  CAS  Google Scholar 

  • Buckley NE, McCoy KL, Mezey E, Bonner T, Zimmer A, Felder CC, Glass M, Zimmer A (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur J Pharmacol 396:141–149

    Article  PubMed  CAS  Google Scholar 

  • Chan B, Lanyi A, Song HK, Griesbach J, Simarro-Grande M, Poy F, Howie D, Sumegi J, Terhorst C, Eck MJ (2003) SAP couples Fyn to SLAM immune receptors. Nat Cell Biol 5:155–160

    Article  PubMed  CAS  Google Scholar 

  • Chuchawankul S, Shima M, Buckley NE, Hartmann CB, McCoy KL (2004) Role of cannabinoid receptors in inhibiting macrophage costimulatory activity. Int Immunopharmacol 4:265–278

    Article  PubMed  CAS  Google Scholar 

  • Correa F, Mestre L, Docagne F, Guaza C (2005) Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages: role of IL-10 and ERK1/2 kinase signaling. Br J Pharmacol 145:441–448

    Article  PubMed  CAS  Google Scholar 

  • Cyster JG (2005) Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 23:127–159

    Article  PubMed  CAS  Google Scholar 

  • Dalwadi H, Wei B, Schrage M, Spicher K, Su TT, Birnbaumer L, Rawlings DJ, Braun J (2003) B cell developmental requirement for the G alpha i2 gene. J Immunol 170:1707–1715

    PubMed  CAS  Google Scholar 

  • Donahue AC, Hess KL, Ng KL, Fruman DA (2004) Altered splenic B cell subset development in mice lacking phosphoinositide 3-kinase p85alpha. Int Immunol 16:1789–1798

    Article  PubMed  CAS  Google Scholar 

  • Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61

    Article  PubMed  CAS  Google Scholar 

  • Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L (2004) NKT cells: what’s in a name? Nat Rev Immunol 4:231–237

    Article  PubMed  CAS  Google Scholar 

  • Han SB, Moratz C, Huang NN, Kelsall B, Cho H, Shi CS, Schwartz O, Kehrl JH (2005) Rgs1 and Gnai2 regulate the entrance of B lymphocytes into lymph nodes and B cell motility within lymph node follicles. Immunity 22:343–354

    Article  PubMed  CAS  Google Scholar 

  • He J, Gurunathan S, Iwasaki A, Ash-Shaheed B, Kelsall BL (2000) Primary role for Gi protein signaling in the regulation of interleukin 12 production and the induction of T helper cell type 1 responses. J Exp Med 191:1605–1610

    Article  PubMed  CAS  Google Scholar 

  • Hornquist CE, Lu X, Rogers-Fani PM, Rudolph U, Shappell S, Birnbaumer L, Harriman GR (1997) G(alpha)i2-deficient mice with colitis exhibit a local increase in memory CD4+ T cells and proinflammatory Th1-type cytokines. J Immunol 158:1068–1077

    PubMed  CAS  Google Scholar 

  • Huang TT, Zong Y, Dalwadi H, Chung C, Miceli MC, Spicher K, Birnbaumer L, Braun J, Aranda R (2003) TCR-mediated hyper-responsiveness of autoimmune Galphai2(−/−) mice is an intrinsic naive CD4(+) T cell disorder selective for the Galphai2 subunit. Int Immunol 15:1359–1367

    Article  PubMed  CAS  Google Scholar 

  • Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Makriyannis A, Vanderah TW, Mata HP, Malan TP Jr (2005) CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA 102:3093–3098

    Article  PubMed  CAS  Google Scholar 

  • Ishii S, Kihara Y, Shimizu T (2005) Identification of T cell death-associated gene 8 (TDAG8) as a novel acid sensing G-protein-coupled receptor. J Biol Chem 280:9083–9087

    Article  PubMed  CAS  Google Scholar 

  • Jorda MA, Lowenberg B, Delwel R (2003) The peripheral cannabinoid receptor Cb2, a novel oncoprotein, induces a reversible block in neutrophilic differentiation. Blood 101:1336–1343

    Article  PubMed  CAS  Google Scholar 

  • Kabashima K, Saji T, Murata T, Nagamachi M, Matsuoka T, Segi E, Tsuboi K, Sugimoto Y, Kobayashi T, Miyachi Y, Ichikawa A, Narumiya S (2002) The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J Clin Invest 109:883–893

    PubMed  CAS  Google Scholar 

  • Kaser A, Nieuwenhuis EE, Strober W, Mayer L, Fuss I, Colgan S, Blumberg RS (2004) Natural killer T cells in mucosal homeostasis. Ann N Y Acad Sci 1029:154–168

    Article  PubMed  CAS  Google Scholar 

  • Kearney JF (2005) Innate-like B cells. Springer Semin Immunopathol 26:377–383

    Article  PubMed  Google Scholar 

  • Khan WN, Alt FW, Gerstein RM, Malynn BA, Larsson I, Rathbun G, Davidson L, Muller S, Kantor AB, Herzenberg LA (1995) Defective B cell development and function in Btk-deficient mice. Immunity 3:283–299

    Article  PubMed  CAS  Google Scholar 

  • Le LQ, Kabarowski JH, Wong S, Nguyen K, Gambhir SS, Witte ON (2002) Positron emission tomography imaging analysis of G2A as a negative modifier of lymphoid leukemogenesis initiated by the BCR-ABL oncogene. Cancer Cell 1:381–391

    Article  PubMed  CAS  Google Scholar 

  • Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:107–118

    Article  PubMed  CAS  Google Scholar 

  • McKinney MK, Cravatt BF (2005) Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 74:411–432

    Article  PubMed  CAS  Google Scholar 

  • Moser B, Wolf M, Walz A, Loetscher P (2004) Chemokines: multiple levels of leukocyte migration control. Trends Immunol 25:75–84

    Article  PubMed  CAS  Google Scholar 

  • Neuman MG (2004) Signaling for inflammation and repair in inflammatory bowel disease. Rom J Gastroenterol 13:309–316

    PubMed  Google Scholar 

  • Ohman L, Franzen L, Rudolph U, Harriman GR, Hultgren HE (2000) Immune activation in the intestinal mucosa before the onset of colitis in Galphai2-deficient mice. Scand J Immunol 52:80–90

    Article  PubMed  CAS  Google Scholar 

  • Pasquier B, Yin L, Fondaneche MC, Relouzat F, Bloch-Queyrat C, Lambert N, Fischer A, Saint-Basile G, Latour S (2005) Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product. J Exp Med 201:695–701

    Article  PubMed  CAS  Google Scholar 

  • Pear WS, Tu L, Stein PL (2004) Lineage choices in the developing thymus: choosing the T and NKT pathways. Curr Opin Immunol 16:167–173

    Article  PubMed  CAS  Google Scholar 

  • Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884

    Article  PubMed  CAS  Google Scholar 

  • Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347:417–429

    Article  PubMed  CAS  Google Scholar 

  • Powrie F (2004) Immune regulation in the intestine: a balancing act between effector and regulatory T cell responses. Ann N Y Acad Sci 1029:132–141

    Article  PubMed  CAS  Google Scholar 

  • Radu CG, Yang LV, Riedinger M, Au M, Witte ON (2004) T cell chemotaxis to lysophosphatidylcholine through the G2A receptor. Proc Natl Acad Sci USA 101:245–250

    Article  PubMed  CAS  Google Scholar 

  • Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON (2005) Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells. Proc Natl Acad Sci USA 102:1632–1637

    Article  PubMed  CAS  Google Scholar 

  • Rayman N, Lam KH, Laman JD, Simons PJ, Lowenberg B, Sonneveld P, Delwel R (2004) Distinct expression profiles of the peripheral cannabinoid receptor in lymphoid tissues depending on receptor activation status. J Immunol 172:2111–2117

    PubMed  CAS  Google Scholar 

  • Rudolph U, Finegold MJ, Rich SS, Harriman GR, Srinivasan Y, Brabet P, Bradley A, Birnbaumer L (1995) Gi2 alpha protein deficiency: a model of inflammatory bowel disease. J Clin Immunol 15:101S–105S

    Article  PubMed  CAS  Google Scholar 

  • Sacerdote P, Martucci C, Vaccani A, Bariselli F, Panerai AE, Colombo A, Parolaro D, Massi P (2005) The nonpsychoactive component of marijuana cannabidiol modulates chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo and in vitro. J Neuroimmunol 159:97–105

    Article  PubMed  CAS  Google Scholar 

  • Silver L (1995) Mouse genetics concepts and applications. Oxford University Press, New York

    Google Scholar 

  • Sipe JC, Arbour N, Gerber A, Beutler E (2005) Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. J Leukoc Biol 78:231–238

    Article  PubMed  CAS  Google Scholar 

  • Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Zimmer A, Frossard JL, Mach F (2005) Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434:782–786

    Article  PubMed  CAS  Google Scholar 

  • Su TT, Rawlings DJ (2002) Transitional B lymphocyte subsets operate as distinct checkpoints in murine splenic B cell development. J Immunol 168:2101–2110

    PubMed  CAS  Google Scholar 

  • Sumariwalla PF, Gallily R, Tchilibon S, Fride E, Mechoulam R, Feldmann M (2004) A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis. Arthritis Rheum 50:985–998

    Article  PubMed  CAS  Google Scholar 

  • Tedford K, Nitschke L, Girkontaite I, Charlesworth A, Chan G, Sakk V, Barbacid M, Fischer KD (2001) Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling. Nat Immunol 2:548–555

    Article  PubMed  CAS  Google Scholar 

  • Van der Heijden PJ, Stok W (1987) Improved procedure for the isolation of functionally active lymphoid cells from the murine intestine. J Immunol Methods 103:161–167

    Article  PubMed  Google Scholar 

  • Velazquez P, Wei B, Braun J (2004) Surveillance B lymphocytes and mucosal immunoregulation. Springer Semin Immunopathol 26:453–462

    Article  PubMed  Google Scholar 

  • Wei B, Velazquez P, Turovskaya O, Spricher K, Aranda R, Kronenberg M, Birnbaumer L, Braun J (2005) Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets. Proc Natl Acad Sci USA 102:2010–2015

    Article  PubMed  CAS  Google Scholar 

  • Yang LV, Radu CG, Wang L, Riedinger M, Witte ON (2005) Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood 105:1127–1134

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the UCLA Jonsson Comprehensive Cancer Center Flow Cytometry Core Laboratory for their assistance in FACS analysis and Dr. M. Kronenberg for the providing the αGalCer/CD1 tetramer. This study is supported by NIH DK46763 and DK69434 (J. B.), AI58919 (P. V.), GM53933 (N. E. B.), CA16042 (Jonsson Comprehensive Cancer Center Core Flow Facility), and the Crohn’s and Colitis Foundation of America (D. Z. and B. W.).2

Author information

Authors and Affiliations

  1. Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA

    David Ziring

  2. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA

    Bo Wei, Peter Velazquez, Matthew Schrage & Jonathan Braun

  3. Department of Biological Sciences, California State Polytechnic University, Pomona, CA, 91768, USA

    Nancy E. Buckley

Authors
  1. David Ziring
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Velazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthew Schrage
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nancy E. Buckley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jonathan Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan Braun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ziring, D., Wei, B., Velazquez, P. et al. Formation of B and T cell subsets require the cannabinoid receptor CB2. Immunogenetics 58, 714–725 (2006). https://doi.org/10.1007/s00251-006-0138-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-006-0138-x

Keywords

Search

Navigation