Adhesion- and Degranulation-Promoting Adapter Protein Promotes CD8 T Cell Differentiation and Resident Memory Formation and Function during an Acute Infection

Abstract

During acute infections, naïve antigen-specific CD8 T cells are activated and differentiate into effector T cells, the majority of which undergo contraction after pathogen clearance. A small population of CD8 T cells persists as memory to protect against future infections. We investigated the role of adhesion and degranulation promoting adapter protein (ADAP) in promoting CD8 T cell responses to a systemic infection. Naïve antigen-specific CD8 T cells lacking ADAP exhibited a modest expansion defect early after Listeria monocytogenes or vesicular stomatitis virus infection but comparable cytolytic function at the peak of response. However, reduced numbers of ADAP-deficient CD8 T cells were present in the spleen after the peak of the response. ADAP deficiency resulted in a greater frequency of CD127+ CD8 memory precursors in secondary lymphoid organs during the contraction phase. Reduced numbers of ADAP-deficient KLRG1− resident memory CD8 T cell (TRM) precursors were present in a variety of non-lymphoid tissues at the peak of the immune response, and consequently the total numbers of ADAP-deficient TRM were reduced at memory time points. TRM cells that did form in the absence of ADAP were defective in effector molecule expression. ADAP-deficient TRM cells exhibited impaired effector function after Ag re-challenge, correlating with defects in their ability to form T:APC conjugates. However, ADAP-deficient TRM cells responded to TGFβ signals and recruited circulating memory CD8 T cells. Thus, ADAP regulates CD8 T cell differentiation events following acute pathogen challenge that are critical for the formation and select functions of TRM cells in non-lymphoid tissues.

Programmed death ligand‐1 induction restrains the cytotoxic T lymphocyte response against microglia

“…An in vivo CTL assay was performed similarly to previously described studies (Barber, Wherry, & Ahmed, 2003; Clemente, Dominguez, Vieira, Rodrigues, & Amarante‐Mendes, 2013; Fiege, Beura, Burbach, & Shimizu, 2016). Mice (either BALB/c or C57BL/6) were primed with rAd5‐p24 intravenously to generate the effector cell population.…”

ADAP Promotes Degranulation and Migration of NK Cells Primed During in vivo Listeria monocytogenes Infection in Mice

“…Moreover, ADAP plays an important role in T cell receptor-and chemokine receptor-mediated activation of integrins (inside-out signaling) and mediates signals derived from the interaction of integrins on T cells with ligands on target cells (outside-in signaling) (4,5). ADAP-deficient T cells show reduced migration toward chemokines (6), impaired formation of the immunological synapse (4,5) and impaired activation, differentiation and resident memory formation during acute infections (6,7).…”

Engineering T cell response to cancer antigens by choice of focal therapeutic conditions

“…The purified TRP-2 T cells were labeled with 5 lM CellTrace Violet (CTV) in 10% FBS for 15 min at 37 C as previously described [53] prior to incubation with DCs. 1.5 Â 10 5 lysate-loaded DCs and 5Â 10 4 CTV labeled T cells were combined in 96-well tissue culture treated flat bottom plates in the presence of TCPM [54]. After 72 h, T cells were collected from the plates into ice-cold FACS buffer (HBSS containing 2% calf serum and 0.1% sodium azide) by pipetting and stained for 30 min on ice with fluorescently conjugated antibodies.…”