Programming Multifaceted Pulmonary T-Cell Immunity by Combination Adjuvants

Induction of protective mucosal T-cell memory remains a formidable challenge to vaccinologists. Using a novel adjuvant strategy that elicits unusually potent CD8 and CD4 T-cell responses, we have defined the tenets of vaccine-induced pulmonary T-cell immunity. An acrylic acid-based adjuvant (ADJ), in combination with TLR agonists glucopyranosyl lipid adjuvant (GLA) or CpG promoted mucosal imprinting but engaged distinct transcription programs to drive different degrees of terminal differentiation and disparate polarization of TH1/TC1/TH17/TC17 effector/memory T cells. Combination of ADJ with GLA, but not CpG, dampened TCR signaling, mitigated terminal differentiation of effectors and enhanced the development of CD4 and CD8 TRM that protected against H1N1 and H5N1 influenza viruses. Mechanistically, vaccine-elicited CD4 T cells played a vital role in optimal programming of CD8 TRM and anti-viral immunity. Taken together, these findings provide new insights into vaccine-induced multi-faceted mucosal T-cell immunity with significant implications in the development of vaccines against respiratory pathogens. One Sentence Summary Adjuvants Induce Multipronged T-Cell Immunity in the Respiratory Tract.

[1]  K. Foulds,et al.  Monocytes Acquire the Ability to Prime Tissue-Resident T Cells via IL-10-Mediated TGF-β Release , 2019, Cell reports.

[2]  H. Padilla-Quirarte,et al.  Protective Antibodies Against Influenza Proteins , 2019, Front. Immunol..

[3]  M. Betts,et al.  Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy individuals , 2019, Science Immunology.

[4]  Aaron J. Johnson,et al.  PD-1hi CD8+ resident memory T cells balance immunity and fibrotic sequelae , 2019, Science Immunology.

[5]  A. Sant.  The Way Forward: Potentiating Protective Immunity to Novel and Pandemic Influenza Through Engagement of Memory CD4 T Cells , 2019, The Journal of infectious diseases.

[6]  J. Kohlmeier,et al.  Establishment and Maintenance of Conventional and Circulation-Driven Lung-Resident Memory CD8+ T Cells Following Respiratory Virus Infections , 2019, Front. Immunol..

[7]  A. Gounder,et al.  Influenza Pathogenesis: The Effect of Host Factors on Severity of Disease , 2019, The Journal of Immunology.

[8]  A. McDermott,et al.  Helper T‐cell responses and pulmonary fungal infections , 2018, Immunology.

[9]  Jie Tian,et al.  Insight Into Non-Pathogenic Th17 Cells in Autoimmune Diseases , 2018, Front. Immunol..

[10]  D. Portnoy,et al.  STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection. , 2018, Cell reports.

[11]  Jason S. Mitchell,et al.  T Cells in Nonlymphoid Tissues Give Rise to Lymph‐Node‐Resident Memory T Cells , 2018, Immunity.

[12]  J. Harty,et al.  Influenza‐induced lung Trm: not all memories last forever , 2017, Immunology and cell biology.

[13]  A. Cavani,et al.  IL‐17 and IL‐22 in immunity: Driving protection and pathology , 2017, European journal of immunology.

[14]  D. Barber,et al.  Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis. , 2017, Cell reports.

[15]  Xiaodi Wu,et al.  Quality of TCR signaling encoded by differential enhancer affinities for the composite BATF-IRF4 transcription factor complex , 2017, Nature Immunology.

[16]  J. Harty,et al.  Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity , 2017, Science Immunology.

[17]  U. V. von Andrian,et al.  The Chemokine Receptor CX3CR1 Defines Three Antigen-Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis. , 2016, Immunity.

[18]  Y. Kawaoka,et al.  Effective Respiratory CD8 T-Cell Immunity to Influenza Virus Induced by Intranasal Carbomer-Lecithin-Adjuvanted Non-replicating Vaccines , 2016, PLoS pathogens.

[19]  S. Sridhar.  Heterosubtypic T-Cell Immunity to Influenza in Humans: Challenges for Universal T-Cell Influenza Vaccines , 2016, Front. Immunol..

[20]  T. Strutt,et al.  New Insights into the Generation of CD4 Memory May Shape Future Vaccine Strategies for Influenza , 2016, Front. Immunol..

[21]  R. Coler,et al.  Mucosal delivery switches the response to an adjuvanted tuberculosis vaccine from systemic TH1 to tissue-resident TH17 responses without impacting the protective efficacy. , 2015, Vaccine.

[22]  Jacob E. Kohlmeier,et al.  Airway-Resident Memory CD8 T Cells Provide Antigen-Specific Protection against Respiratory Virus Challenge through Rapid IFN-γ Production , 2015, The Journal of Immunology.

[23]  Taeg S. Kim,et al.  The effector T cell response to influenza infection. , 2015, Current topics in microbiology and immunology.

[24]  S. Kaech,et al.  CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. , 2014, Immunity.

[25]  T. Randall,et al.  Prolonged antigen presentation by immune complex–binding dendritic cells programs the proliferative capacity of memory CD8 T cells , 2014, Journal of Experimental Medicine.

[26]  Raymond M. Welsh,et al.  Graded Levels of IRF4 Regulate CD8+ T Cell Differentiation and Expansion, but Not Attrition, in Response to Acute Virus Infection , 2014, The Journal of Immunology.

[27]  Virander S. Chauhan,et al.  Production and Preclinical Evaluation of Plasmodium falciparum MSP-119 and MSP-311 Chimeric Protein, PfMSP-Fu24 , 2014, Clinical and Vaccine Immunology.

[28]  D. Masopust,et al.  Editorial: Pulmonary resident memory CD8 T cells: here today, gone tomorrow , 2014, Journal of leukocyte biology.

[29]  S. Kaech,et al.  Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus. , 2013, Immunity.

[30]  S. Jameson,et al.  Transcriptional downregulation of S1pr1 is required for establishment of resident memory CD8+ T cells , 2013, Nature Immunology.

[31]  J. Mascola,et al.  Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates , 2013, Journal of Virology.

[32]  Helder I Nakaya,et al.  Immunity to viruses: learning from successful human vaccines , 2013, Immunological reviews.

[33]  Philip R. Johnson,et al.  Accelerating Next-Generation Vaccine Development for Global Disease Prevention , 2013, Science.

[34]  T. Strutt,et al.  Multiple Redundant Effector Mechanisms of CD8+ T Cells Protect against Influenza Infection , 2013, The Journal of Immunology.

[35]  U. Klein,et al.  TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation , 2012, Proceedings of the National Academy of Sciences.

[36]  T. Strutt,et al.  Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms. , 2012, The Journal of clinical investigation.

[37]  C. Foged,et al.  License to kill: Formulation requirements for optimal priming of CD8(+) CTL responses with particulate vaccine delivery systems. , 2012, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[38]  S. Kern,et al.  Th17 cells are long lived and retain a stem cell-like molecular signature. , 2011, Immunity.

[39]  G. Neumann,et al.  Replication-incompetent influenza A viruses that stably express a foreign gene. , 2011, The Journal of general virology.

[40]  Nicole R. Cunningham,et al.  T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse , 2011, The Journal of experimental medicine.

[41]  R. Coffman,et al.  Vaccine adjuvants: putting innate immunity to work. , 2010, Immunity.

[42]  Jongdae Lee,et al.  TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice. , 2010, The Journal of clinical investigation.

[43]  R. Ahmed,et al.  CD8 T-cell memory differentiation during acute and chronic viral infections. , 2010, Advances in experimental medicine and biology.

[44]  S. Jameson,et al.  Diversity in T cell memory: an embarrassment of riches. , 2009, Immunity.

[45]  K. Legge,et al.  Cutting Edge: Contribution of Lung-Resident T Cell Proliferation to the Overall Magnitude of the Antigen-Specific CD8 T Cell Response in the Lungs following Murine Influenza Virus Infection1 , 2009, The Journal of Immunology.

[46]  H. Ochs,et al.  IL-10 Deficiency Unleashes an Influenza-Specific Th17 Response and Enhances Survival against High-Dose Challenge1 , 2009, The Journal of Immunology.

[47]  T. Strutt,et al.  Tc17, a Unique Subset of CD8 T Cells That Can Protect against Lethal Influenza Challenge1 , 2009, The Journal of Immunology.

[48]  Surojit Sarkar,et al.  Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates , 2008, The Journal of experimental medicine.

[49]  B. Zheng,et al.  Rectification of Age-Associated Deficiency in Cytotoxic T Cell Response to Influenza A Virus by Immunization with Immune Complexes , 2007, The Journal of Immunology.

[50]  Nikhil S. Joshi,et al.  Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. , 2007, Immunity.

[51]  J. Harty,et al.  Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(+) T cell response to infection. , 2007, Immunity.

[52]  J. Harty,et al.  Inflaming the CD8+ T cell response. , 2006, Immunity.

[53]  Bali Pulendran,et al.  Translating Innate Immunity into Immunological Memory: Implications for Vaccine Development , 2006, Cell.

[54]  J. Leiden,et al.  LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. , 1997, Science.

[55]  David Gray,et al.  Immunological Memory and Protective Immunity: Understanding Their Relation , 1996, Science.

[56]  Peter C. Doherty,et al.  Virus-specific CD8+ T-cell memory determined by clonal burst size , 1994, Nature.

[57]  D. Hannant,et al.  Antigenicity and immunogenicity of equine influenza vaccines containing a Carbomer adjuvant , 1994, Epidemiology and Infection.

[58]  E. Foni,et al.  The ability by different preparations of porcine parvovirus to enhance humoral immunity in swine and guinea pigs. , 1988, Microbiologica.