tetano
Editor, Senior Moderator
Front Immunol
. 2023 Feb 21;13:1041552.
doi: 10.3389/fimmu.2022.1041552. eCollection 2022.
ICAMs are dispensable for influenza clearance and anti-viral humoral and cellular immunity
Stav Kozlovski[SUP] 1 [/SUP], Ofer Regev[SUP] 1 [/SUP], Anita Sapoznikov[SUP] 2 [/SUP], Marina Kizner[SUP] 1 [/SUP], Hagit Achdout[SUP] 2 [/SUP], Ekaterina Petrovich-Kopitman[SUP] 3 [/SUP], Jacob Elkahal[SUP] 4 [/SUP], Yoseph Addadi[SUP] 3 [/SUP], Fernanda Vargas E Silva Castanheira[SUP] 5 [/SUP], Sara W Feigelson[SUP] 1 [/SUP], Paul Kubes[SUP] 5 [/SUP], Noam Erez[SUP] 2 [/SUP], Natalio Garbi[SUP] 6 [/SUP], Ronen Alon[SUP] 1 [/SUP]
Affiliations
Abstract
αLβ2 (LFA-1) mediated interactions with ICAM-1 and ICAM-2 predominate leukocyte-vascular interactions, but their functions in extravascular cell-cell communications is still debated. The roles of these two ligands in leukocyte trafficking, lymphocyte differentiation, and immunity to influenza infections were dissected in the present study. Surprisingly, double ICAM-1 and ICAM-2 knock out mice (herein ICAM-1/2[SUP]-/-[/SUP] mice) infected with a lab adapted H1N1 influenza A virus fully recovered from infection, elicited potent humoral immunity, and generated normal long lasting anti-viral CD8[SUP]+[/SUP] T cell memory. Furthermore, lung capillary ICAMs were dispensable for both NK and neutrophil entry to virus infected lungs. Mediastinal lymph nodes (MedLNs) of ICAM-1/2[SUP]-/-[/SUP] mice poorly recruited naïve T cells and B lymphocytes but elicited normal humoral immunity critical for viral clearance and effective CD8[SUP]+[/SUP] differentiation into IFN-γ producing T cells. Furthermore, whereas reduced numbers of virus specific effector CD8[SUP]+[/SUP] T cells accumulated inside infected ICAM-1/2[SUP]-/-[/SUP] lungs, normal virus-specific T[SUB]RM[/SUB] CD8[SUP]+[/SUP] cells were generated inside these lungs and fully protected ICAM-1/2[SUP]-/-[/SUP] mice from secondary heterosubtypic infections. B lymphocyte entry to the MedLNs and differentiation into extrafollicular plasmablasts, producing high affinity anti-influenza IgG2a antibodies, were also ICAM-1 and ICAM-2 independent. A potent antiviral humoral response was associated with accumulation of hyper-stimulated cDC2s in ICAM null MedLNs and higher numbers of virus-specific T follicular helper (Tfh) cells generated following lung infection. Mice selectively depleted of cDC ICAM-1 expression supported, however, normal CTL and Tfh differentiation following influenza infection, ruling out essential co-stimulatory functions of DC ICAM-1 in CD8[SUP]+[/SUP] and CD4[SUP]+[/SUP] T cell differentiation. Collectively our findings suggest that lung ICAMs are dispensable for innate leukocyte trafficking to influenza infected lungs, for the generation of peri-epithelial T[SUB]RM[/SUB] CD8[SUP]+[/SUP] cells, and long term anti-viral cellular immunity. In lung draining LNs, although ICAMs promote lymphocyte homing, these key integrin ligands are not required for influenza-specific humoral immunity or generation of IFN-γ effector CD8[SUP]+[/SUP] T cells. In conclusion, our findings suggest unexpected compensatory mechanisms that orchestrate protective anti-influenza immunity in the absence of vascular and extravascular ICAMs.
Keywords: endothelium; inflammation; integrins; leukocyte trafficking; memory.
. 2023 Feb 21;13:1041552.
doi: 10.3389/fimmu.2022.1041552. eCollection 2022.
ICAMs are dispensable for influenza clearance and anti-viral humoral and cellular immunity
Stav Kozlovski[SUP] 1 [/SUP], Ofer Regev[SUP] 1 [/SUP], Anita Sapoznikov[SUP] 2 [/SUP], Marina Kizner[SUP] 1 [/SUP], Hagit Achdout[SUP] 2 [/SUP], Ekaterina Petrovich-Kopitman[SUP] 3 [/SUP], Jacob Elkahal[SUP] 4 [/SUP], Yoseph Addadi[SUP] 3 [/SUP], Fernanda Vargas E Silva Castanheira[SUP] 5 [/SUP], Sara W Feigelson[SUP] 1 [/SUP], Paul Kubes[SUP] 5 [/SUP], Noam Erez[SUP] 2 [/SUP], Natalio Garbi[SUP] 6 [/SUP], Ronen Alon[SUP] 1 [/SUP]
Affiliations
- PMID: 36895258
- PMCID: PMC9988921
- DOI: 10.3389/fimmu.2022.1041552
Abstract
αLβ2 (LFA-1) mediated interactions with ICAM-1 and ICAM-2 predominate leukocyte-vascular interactions, but their functions in extravascular cell-cell communications is still debated. The roles of these two ligands in leukocyte trafficking, lymphocyte differentiation, and immunity to influenza infections were dissected in the present study. Surprisingly, double ICAM-1 and ICAM-2 knock out mice (herein ICAM-1/2[SUP]-/-[/SUP] mice) infected with a lab adapted H1N1 influenza A virus fully recovered from infection, elicited potent humoral immunity, and generated normal long lasting anti-viral CD8[SUP]+[/SUP] T cell memory. Furthermore, lung capillary ICAMs were dispensable for both NK and neutrophil entry to virus infected lungs. Mediastinal lymph nodes (MedLNs) of ICAM-1/2[SUP]-/-[/SUP] mice poorly recruited naïve T cells and B lymphocytes but elicited normal humoral immunity critical for viral clearance and effective CD8[SUP]+[/SUP] differentiation into IFN-γ producing T cells. Furthermore, whereas reduced numbers of virus specific effector CD8[SUP]+[/SUP] T cells accumulated inside infected ICAM-1/2[SUP]-/-[/SUP] lungs, normal virus-specific T[SUB]RM[/SUB] CD8[SUP]+[/SUP] cells were generated inside these lungs and fully protected ICAM-1/2[SUP]-/-[/SUP] mice from secondary heterosubtypic infections. B lymphocyte entry to the MedLNs and differentiation into extrafollicular plasmablasts, producing high affinity anti-influenza IgG2a antibodies, were also ICAM-1 and ICAM-2 independent. A potent antiviral humoral response was associated with accumulation of hyper-stimulated cDC2s in ICAM null MedLNs and higher numbers of virus-specific T follicular helper (Tfh) cells generated following lung infection. Mice selectively depleted of cDC ICAM-1 expression supported, however, normal CTL and Tfh differentiation following influenza infection, ruling out essential co-stimulatory functions of DC ICAM-1 in CD8[SUP]+[/SUP] and CD4[SUP]+[/SUP] T cell differentiation. Collectively our findings suggest that lung ICAMs are dispensable for innate leukocyte trafficking to influenza infected lungs, for the generation of peri-epithelial T[SUB]RM[/SUB] CD8[SUP]+[/SUP] cells, and long term anti-viral cellular immunity. In lung draining LNs, although ICAMs promote lymphocyte homing, these key integrin ligands are not required for influenza-specific humoral immunity or generation of IFN-γ effector CD8[SUP]+[/SUP] T cells. In conclusion, our findings suggest unexpected compensatory mechanisms that orchestrate protective anti-influenza immunity in the absence of vascular and extravascular ICAMs.
Keywords: endothelium; inflammation; integrins; leukocyte trafficking; memory.