CD4 T Cells Require Either B Cells or CD8 T Cells to Control Spread and Pathogenesis of a Neurotropic Infection

Overview

Journal Virology

Specialty Microbiology

Date 2016 Sep 28

PMID 27677156

Citations 6

Authors

Andreas C Solomos

Kevin J ORegan

Glenn F Rall

Affiliations

Soon will be listed here.

Abstract

Immunity within the brain, specifically to virus-infected neurons, must be controlled to prevent neuron loss and impairment, though the process by which this occurs remains unclear. Here, we use a mouse model of neuron-restricted measles virus infection, in which immunocompetent adults survive challenge, whereas T and B cell-deficient mice succumb. This model allowed us to more precisely define the contributions of CD4 T cells, CD8 T cells, and B cells in neuroprotection. Both B cell knockout mice and mice depleted of CD8 T cells survive challenge and show no signs of illness, though are less able to control viral replication than immunocompetent mice. In contrast, depletion of CD4 T cells results in disease and death in all infected mice, though the kinetics of illness are delayed compared to RAG knockout mice. Our data suggest a coordinated interplay of adaptive immune components, which collectively controls viral spread and limits neuropathogenesis.

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References

ODonnell L, Henkins K, Kulkarni A, Matullo C, Balachandran S, Pattisapu A . Interferon gamma induces protective non-canonical signaling pathways in primary neurons. J Neurochem. 2015; 135(2):309-22. PMC: 4809142. DOI: 10.1111/jnc.13250. View

Dalton D, Keshav S, Figari I, Bradley A, Stewart T . Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993; 259(5102):1739-42. DOI: 10.1126/science.8456300. View

Kitamura D, Roes J, Kuhn R, Rajewsky K . A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature. 1991; 350(6317):423-6. DOI: 10.1038/350423a0. View

Hickey W, Hsu B, Kimura H . T-lymphocyte entry into the central nervous system. J Neurosci Res. 1991; 28(2):254-60. DOI: 10.1002/jnr.490280213. View

Tishon A, Lewicki H, Andaya A, McGavern D, Martin L, Oldstone M . CD4 T cell control primary measles virus infection of the CNS: regulation is dependent on combined activity with either CD8 T cells or with B cells: CD4, CD8 or B cells alone are ineffective. Virology. 2006; 347(1):234-45. DOI: 10.1016/j.virol.2006.01.050. View

ODonnell L, Rall G . Blue moon neurovirology: the merits of studying rare CNS diseases of viral origin. J Neuroimmune Pharmacol. 2010; 5(3):443-55. DOI: 10.1007/s11481-010-9200-4. View

Sarmiento M, Glasebrook A, Fitch F . IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980; 125(6):2665-72. View

Binder G, Griffin D . Interferon-gamma-mediated site-specific clearance of alphavirus from CNS neurons. Science. 2001; 293(5528):303-6. DOI: 10.1126/science.1059742. View

Komatsu T, Bi Z, Reiss C . Interferon-gamma induced type I nitric oxide synthase activity inhibits viral replication in neurons. J Neuroimmunol. 1996; 68(1-2):101-8. DOI: 10.1016/0165-5728(96)00083-5. View

10.

Louveau A, Smirnov I, Keyes T, Eccles J, Rouhani S, Peske J . Structural and functional features of central nervous system lymphatic vessels. Nature. 2015; 523(7560):337-41. PMC: 4506234. DOI: 10.1038/nature14432. View

11.

Grusby M, Johnson R, Papaioannou V, Glimcher L . Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science. 1991; 253(5026):1417-20. DOI: 10.1126/science.1910207. View

12.

Shinkai Y, Rathbun G, Lam K, Oltz E, Stewart V, Mendelsohn M . RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992; 68(5):855-67. DOI: 10.1016/0092-8674(92)90029-c. View

13.

Rose R, Vorobyeva A, Skipworth J, Nicolas E, Rall G . Altered levels of STAT1 and STAT3 influence the neuronal response to interferon gamma. J Neuroimmunol. 2007; 192(1-2):145-56. PMC: 2180831. DOI: 10.1016/j.jneuroim.2007.10.007. View

14.

Ransohoff R, Engelhardt B . The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012; 12(9):623-35. DOI: 10.1038/nri3265. View

15.

Podolsky M, Solomos A, Durso L, Evans S, Rall G, Rose R . Extended JAK activation and delayed STAT1 dephosphorylation contribute to the distinct signaling profile of CNS neurons exposed to interferon-gamma. J Neuroimmunol. 2012; 251(1-2):33-8. PMC: 3678282. DOI: 10.1016/j.jneuroim.2012.06.006. View

16.

Wilde D, Marrack P, Kappler J, Dialynas D, Fitch F . Evidence implicating L3T4 in class II MHC antigen reactivity; monoclonal antibody GK1.5 (anti-L3T4a) blocks class II MHC antigen-specific proliferation, release of lymphokines, and binding by cloned murine helper T lymphocyte lines. J Immunol. 1983; 131(5):2178-83. View

17.

Cserr H, Knopf P . Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view. Immunol Today. 1992; 13(12):507-12. DOI: 10.1016/0167-5699(92)90027-5. View

18.

Solomos A, Rall G . Get It through Your Thick Head: Emerging Principles in Neuroimmunology and Neurovirology Redefine Central Nervous System "Immune Privilege". ACS Chem Neurosci. 2016; 7(4):435-41. DOI: 10.1021/acschemneuro.5b00336. View

19.

Patterson C, Lawrence D, Echols L, Rall G . Immune-mediated protection from measles virus-induced central nervous system disease is noncytolytic and gamma interferon dependent. J Virol. 2002; 76(9):4497-506. PMC: 155105. DOI: 10.1128/jvi.76.9.4497-4506.2002. View

20.

Muller U, Steinhoff U, Reis L, Hemmi S, Pavlovic J, Zinkernagel R . Functional role of type I and type II interferons in antiviral defense. Science. 1994; 264(5167):1918-21. DOI: 10.1126/science.8009221. View