BTLA Interaction with HVEM Expressed on CD8+ T Cells Promotes Survival and Memory Generation in Response to a Bacterial Infection

The B and T lymphocyte attenuator (BTLA) is an Ig super family member that binds to the herpes virus entry mediator (HVEM), a TNF receptor super family (TNFRSF) member. Engagement of BTLA by HVEM triggers inhibitory signals, although recent evidence indicates that BTLA also may act as an activating ligand for HVEM. In this study, we reveal a novel role for the BTLA-HVEM pathway in promoting the survival of activated CD8+ T cells in the response to an oral microbial infection. Our data show that both BTLA- and HVEM-deficient mice infected with Listeria monocytogenes had significantly reduced numbers of primary effector and memory CD8+ T cells, despite normal proliferation and expansion compared to controls. In addition, blockade of the BTLA-HVEM interaction early in the response led to significantly reduced numbers of antigen-specific CD8+ T cells. HVEM expression on the CD8+ T cells as well as BTLA expression on a cell type other than CD8+ T lymphocytes, was required. Collectively, our data demonstrate that the function of the BTLA-HVEM pathway is not limited to inhibitory signaling in T lymphocytes, and instead, that BTLA can provide crucial, HVEM-dependent signals that promote survival of antigen activated CD8+ T cell during bacterial infection.

[1]  C. Ware,et al.  Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations , 2011, The Journal of experimental medicine.

[2]  K. Tamada,et al.  Dichotomous regulation of GVHD through bidirectional functions of the BTLA-HVEM pathway. , 2011, Blood.

[3]  H. Ertl,et al.  Augmentation of Primary Influenza A Virus-Specific CD8+ T Cell Responses in Aged Mice through Blockade of an Immunoinhibitory Pathway , 2010, The Journal of Immunology.

[4]  W. Britton,et al.  LIGHT contributes to early but not late control of Mycobacterium tuberculosis infection. , 2010, International immunology.

[5]  Matthew G. Macauley,et al.  T Cell Intrinsic Heterodimeric Complexes between HVEM and BTLA Determine Receptivity to the Surrounding Microenvironment1 , 2009, The Journal of Immunology.

[6]  Yang Wang,et al.  B and T Lymphocyte Attenuator Tempers Early Infection Immunity1 , 2009, The Journal of Immunology.

[7]  yang-xin fu,et al.  Cutting Edge: B and T Lymphocyte Attenuator Signaling on NKT Cells Inhibits Cytokine Release and Tissue Injury in Early Immune Responses1 , 2009, The Journal of Immunology.

[8]  Matthew G. Macauley,et al.  Unconventional ligand activation of herpesvirus entry mediator signals cell survival , 2009, Proceedings of the National Academy of Sciences.

[9]  C. Ware,et al.  Cross-regulation between herpesviruses and the TNF superfamily members , 2008, Nature Reviews Immunology.

[10]  K. Murphy,et al.  B and T Lymphocyte Attenuator Regulates T Cell Survival in the Lung1 , 2008, The Journal of Immunology.

[11]  Kenneth M. Murphy,et al.  A crucial role for HVEM and BTLA in preventing intestinal inflammation , 2008, The Journal of experimental medicine.

[12]  E. Wherry,et al.  Targeting of antigen to the herpesvirus entry mediator augments primary adaptive immune responses , 2008, Nature Medicine.

[13]  G. Freeman,et al.  CD160 inhibits activation of human CD4+ T cells through interaction with herpesvirus entry mediator , 2008, Nature Immunology.

[14]  K. Murphy,et al.  Unexpected Role of B and T Lymphocyte Attenuator in Sustaining Cell Survival during Chronic Allostimulation , 2007, The Journal of Immunology.

[15]  O. Boyman,et al.  B and T lymphocyte attenuator regulates CD8+ T cell–intrinsic homeostasis and memory cell generation , 2007, Nature Immunology.

[16]  Michael Y. Gerner,et al.  Signals required for programming effector and memory development by CD8+ T cells , 2006, Immunological reviews.

[17]  J. Gommerman,et al.  LIGHT is dispensable for CD4+ and CD8+ T cell and antibody responses to influenza A virus in mice. , 2006, International immunology.

[18]  K. Murphy,et al.  Cutting Edge: B and T Lymphocyte Attenuator and Programmed Death Receptor-1 Inhibitory Receptors Are Required for Termination of Acute Allergic Airway Inflammation1 , 2006, The Journal of Immunology.

[19]  K. Murphy,et al.  Differential Effects of B and T Lymphocyte Attenuator and Programmed Death-1 on Acceptance of Partially versus Fully MHC-Mismatched Cardiac Allografts1 , 2005, The Journal of Immunology.

[20]  C. Benedict,et al.  Evolutionarily divergent herpesviruses modulate T cell activation by targeting the herpesvirus entry mediator cosignaling pathway. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  K. Pfeffer,et al.  The role of herpesvirus entry mediator as a negative regulator of T cell-mediated responses. , 2005, The Journal of clinical investigation.

[22]  Wenjun Ouyang,et al.  A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Kaye,et al.  References Subscriptions Permissions Email Alerts An Inhibitory Ig Superfamily Protein Expressed by Lymphocytes and APCs Is Also an Early Marker of Thymocyte Positive Selection , 2013 .

[24]  P. Spear,et al.  Herpes simplex virus: receptors and ligands for cell entry , 2004, Cellular microbiology.

[25]  M. Croft.  Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? , 2003, Nature Reviews Immunology.

[26]  J. Allison,et al.  BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1 , 2003, Nature Immunology.

[27]  C. Schmidt,et al.  LIGHT-deficiency impairs CD8+ T cell expansion, but not effector function. , 2003, International immunology.

[28]  Y. Zhai,et al.  LIGHT, a new member of the TNF superfamily. , 2002, Journal of biological regulators and homeostatic agents.

[29]  J. Alferink,et al.  Targeted Disruption of LIGHT Causes Defects in Costimulatory T Cell Activation and Reveals Cooperation with Lymphotoxin β in Mesenteric Lymph Node Genesis , 2002, The Journal of experimental medicine.

[30]  M. Fiscella,et al.  Cutting Edge: Selective Impairment of CD8+ T Cell Function in Mice Lacking the TNF Superfamily Member LIGHT , 2002, The Journal of Immunology.

[31]  Hao Shen,et al.  Organ-Specific Regulation of the CD8 T Cell Response to Listeria monocytogenes Infection1 , 2001, The Journal of Immunology.

[32]  C. Ware,et al.  LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. , 1998, Immunity.

[33]  S. Targan,et al.  Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients. , 1997, Journal of immunology.