ICAMs Are Not Obligatory for Functional Immune Synapses between Naive CD4 T Cells and Lymph Node DCs

Abstract

Protective immune responses depend on the formation of immune synapses between T cells and antigen-presenting cells (APCs). The two main LFA-1 ligands, ICAM-1 and ICAM-2, are co-expressed on many cell types, including APCs and blood vessels. Although these molecules were suggested to be key players in immune synapses studied in vitro, their contribution to helper T cell priming in vivo is unclear. Here, we used transgenic mice and intravital imaging to examine the role of dendritic cell (DC) ICAM-1 and ICAM-2 in naive CD4 T cell priming and differentiation in skin-draining lymph nodes. Surprisingly, ICAM deficiency on endogenous CD40-stimulated lymph node DCs did not impair their ability to arrest and prime CD4 lymphocyte activation and differentiation into Th1 and Tfh effectors. Thus, functional T cell receptor (TCR)-specific helper T cell synapses with antigen-presenting DCs and subsequent proliferation and early differentiation into T effectors do not require LFA-1-mediated T cell adhesiveness to DC ICAMs.

Cytoskeletal tension actively sustains the migratory T cell synaptic contact

“…Similarly, activation of the integrin LFA1 is a prerequisite for successful synaptic engagement, but is not needed for maintenance of the synapse. These results support a recent finding that the LFA1-ICAM1 interaction is not necessary for stable CD4 T cell-DC synapses in the lymph node (Feigelson et al, 2018). The physiological implications are that T cells may use integrin-based adhesion to initiate synaptic contacts with selective cellular partners (Feigelson et al, 2018;Zaretsky et al, 2017), but maintain adhesion using lateral tensional mechanisms within the cell provided by the dynamic cytoskeletal arrangements comprising foci nucleation and acto-myosin contractions described here.…”

Stable contacts of naïve CD4 T cells with migratory dendritic cells are ICAM-1-dependent but dispensable for proliferation in vivo

“…In this work we found that combined ICAM-1 and ICAM-2 deficiency on resident lymph node DCs stimulated with anti CD40 and immunized with soluble antigen did not impair their ability to arrest naïve CD4 lymphocytes entering these lymph nodes from blood and did not abrogate their subsequent in vivo differentiation into Th1 and Tfh effectors [13]. Our conclusion was that functional T cell receptor (TCR)-triggered contacts between naïve CD4 T cells and resident antigenpresenting lymph node DCs do not require the presence of ICAM-1 or ICAM-2 on resident lymph node DCs [13]. This study suggested that the ability of naïve T cells to in situ activate their LFA-1 adhesiveness in response to potent TCR signals, a processed termed LFA-1 inside out activation [14], is much more restricted than previously thought [15,16].…”

“…This study suggested that the ability of naïve T cells to in situ activate their LFA-1 adhesiveness in response to potent TCR signals, a processed termed LFA-1 inside out activation [14], is much more restricted than previously thought [15,16]. The configuration of that study involved soluble antigen presented to naive OT-II CD4 T cells by essentially all DCs residing within the T zone of popliteal draining lymph nodes [13]. The failure to detect any contribution of the LFA-1-ICAM-1 and 2 axis to CD4 T cell proliferation and differentiation was attributed to individual naïve T cells engaging in highly frequent contacts with the numerous antigen presenting DCs they encountered, and reaching a TCR activation threshold by serial short-lived encounters with multiple DCs [3,17,18].…”

“…However, the contribution of this molecular axis to T-DC communication was mostly investigated in vitro [9]. The specific in vivo contributions of LFA-1-ICAM interactions to naïve T cell proliferation are still disputed [10][11][12][13], due to the lack of adequate genetic models of APC-type specific ICAM knock out mice.…”

“…To address this issue, we have recently used chimeric mice expressing normal non-hematopoietic ICAM-1 and ICAM-2 reconstituted with immune cells deficient in both ICAMs [13]. In this work we found that combined ICAM-1 and ICAM-2 deficiency on resident lymph node DCs stimulated with anti CD40 and immunized with soluble antigen did not impair their ability to arrest naïve CD4 lymphocytes entering these lymph nodes from blood and did not abrogate their subsequent in vivo differentiation into Th1 and Tfh effectors [13]. Our conclusion was that functional T cell receptor (TCR)-triggered contacts between naïve CD4 T cells and resident antigenpresenting lymph node DCs do not require the presence of ICAM-1 or ICAM-2 on resident lymph node DCs [13].…”