Tissue instruction for migration and retention of TRM cells

Abstract

During infection, a subset of effector T cells seeds the lymphoid and non-lymphoid tissues and gives rise to tissue-resident memory T cells (TRM). Recent findings have provided insight into the molecular and cellular mechanisms underlying tissue instruction of TRM cell homing, as well as the programs involved in their retention and maintenance. We review these findings here, highlighting both common features and distinctions between CD4 TRM and CD8 TRM cells. In this context we examine the role of memory lymphocyte clusters (MLCs), and propose that the MLCs serve as an immediate response center consisting of TRM cells on standby, capable of detecting incoming pathogens and mounting robust local immune responses to contain and limit the spread of infectious agents.

Figure 1. Overview of the steps involved in recruitment of CD8 TRM precursors to the inflamed tissue

(Step 1: Rolling) CD8 Teff slow down and roll on the endothelium of the postcapillary venule at the site of inflammation. P-selectin and E-selectin expressed by endothelial cells bind to P-selectin ligand and E-selectin ligand on CD8 Teff, respectively. (Step 2: Chemokine activation) CD4 Teff enter the tissue in response to infection and secrete IFN-γ, which activates dendritic cells to secrete CXCL9 and CXCL10. In addition, endothelial cells in response to type I interferons secrete CXCL10. These chemokines are displayed by the endothelial cells to recruit CD8 Teff. (Step 3: Arrest) Chemokine engagement of the receptor CXCR3 activates integrins, VLA-4 (α4β1) and LFA1 (αLβ2), on CD8 Teff through inside out signaling, and enables the lymphocytes to adhere to the endothelium and come to a complete stop. (Step 4: Transendothelial migration) Arrested lymphocytes must cross the endothelial layer in order to get access to the tissue. Teff use molecules such as PECAM, CD99, LFA1 which bind to PECAM, CD99 and ICAM-1/JAM-1 on endothelial cells, respectively, to crawl between the endothelial cells to enter the tissue. (Step 5: Migration toward infected cells) Once inside the tissue, Teff are recruited to the site of infection by migration towards chemokine gradient. Infected cells, as well as type I interferons, can induce secretion of chemokines such as CXCL10 that mediate this last step.

Figure 2. Model for retention of CD4 T_RM and CD8 T_RM in the memory lymphocyte clusters

Once inside the tissue, CD4 Teff and CD8 Teff undergo further differentiation to become T_RM. In the epithelial layer, CD8 T_RM precursor receives TGF-β signal from the surrounding epithelial cells, which induces CD103 expression. CD103 binds to E-cadherin to mediate stable interaction. CD8 T_RMprecursors also induce CD69 expression, which binds to S1P1 and degrades it. T_RM precursors also downregulate KLF2, a transcription factor required for expression of S1P1 and CCR7. Below the epithelial layer, both CD8 T_RM and CD4 T_RM are retained in memory lymphocyte clusters (MLCs) consisting of T_RM and tissue resident macrophages and dendritic cells. Small amount of antigen is likely retained and presented by macrophages, which induce constitutive secretion of low levels of IFN-γ from CD4 T_RM. IFN-γ binds to its receptor on macrophages, inducing expression of CCL5 and CXCL9. CCL5 binds to its receptor on CD4 T_RM, enabling their interaction with macrophages through a yet to be identified integrin(s). CXCL9 binds to CXCR3 on CD8 T_RM, which helps retain these cells within the MLCs. MLCs are found in the lower female reproductive tract after HSV-2 infection (humans, mice and guinea pigs) or SIV infection (in primates), in the brain after T. gondii infection (mice), in the alveoli after intratrachial LCMV infection and in the salivary gland after MCMV infection (mice).