The CD3 ζ Subunit of the T Cell Receptor is Required for an Efficient Immune Response During Bacterial Infection

Abstract

The T cell receptor (TCR) complex is comprised of a ligand binding αβ heterodimer and two signaling modules, CD3 ζζ and CD3 γε/δε. Each signaling subunit has at least one copy of an ITAM signaling motif. TCR engagement results in bi‐phosphorylation of the ITAM on tyrosine residues, allowing ZAP‐70 to complex. This initiates an intracellular signaling cascade, leading to T cell activation and effector function.We generated CD3 ζ transgenic mice (YF1‐6) lacking all forms of phospho‐ζ. Previous data have shown that phospho‐ζ is not required for T cell development or signaling. Conversely, after TCR stimulation, CD8+ T cells from YF1‐6 mice produce 2‐fold less IFN‐γ than C57BL/6 mice. To determine the impact of this difference, we established a Listeria monocytogenes (LM) infection model. We found that YF1‐6 mice could not clear primary LM infections and had 5 to 50‐fold higher CFUs in the liver and spleen compared to control mice. Yet, after secondary infection, YF1‐6 and C57BL/6 mice cleared the bacteria. This suggests that phospho‐ζ is required for innate cell function during LM infection. We are examining whether this results from aberrant CD8+ T or NK cell function, as both populations are thought to be important for early IFN‐γ production and LM clearance. Defining the role of phospho‐ζ during innate immune responses to infections may reveal new therapeutic targets. Supported by NIH T32 AI005284‐28, AI042953, AI45764