Retention of Ag‐specific memory CD4⁺ T cells in the draining lymph node indicates lymphoid tissue resident memory populations

Abstract

Several different memory T‐cell populations have now been described based upon surface receptor expression and migratory capabilities. Here we have assessed murine endogenous memory CD4+ T cells generated within a draining lymph node and their subsequent migration to other secondary lymphoid tissues. Having established a model response targeting a specific peripheral lymph node, we temporally labelled all the cells within draining lymph node using photoconversion. Tracking of photoconverted and non‐photoconverted Ag‐specific CD4+ T cells revealed the rapid establishment of a circulating memory population in all lymph nodes within days of immunisation. Strikingly, a resident memory CD4+ T cell population became established in the draining lymph node and persisted for several months in the absence of detectable migration to other lymphoid tissue. These cells most closely resembled effector memory T cells, usually associated with circulation through non‐lymphoid tissue, but here, these cells were retained in the draining lymph node. These data indicate that lymphoid tissue resident memory CD4+ T‐cell populations are generated in peripheral lymph nodes following immunisation.

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…26,189–191 Similar as T RM isolated from non-lymphoid organs, these secondary lymphoid organ CD4 + T RM express higher levels of CD69 and lower levels of S1pr1 than their circulating counterparts. In contrast to the widely accepted notion that secondary lymphoid organs are mainly occupied by circulating T cells, antigen-specific CD4 + memory T cells residing in the draining lymph nodes are largely sessile after immunization.…”

“…In contrast to the widely accepted notion that secondary lymphoid organs are mainly occupied by circulating T cells, antigen-specific CD4 + memory T cells residing in the draining lymph nodes are largely sessile after immunization. 191 Further, similar CD4 + T RM cells are present in the secondary lymphoid organs of naïve specific pathogen free mice presumably due to prolonged TCR stimulation by self-antigens and microbiome-derived antigens. The population of secondary lymphoid organ CD4 + T RM expands with age.…”

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

“…Tfh cells can remain for many months in the original draining lymph node where persistent antigen is likely to maintain them in an active state. These cells rapidly expand upon re‐challenge and may represent a population of lymph node resident memory cells as they can express CD69 58, 59, 60. However, this reliance on antigen suggests that these lymph node resident Tfh cells may not represent ‘true resting memory cells’.…”

Chemokines: Critical Regulators of Memory T Cell Development, Maintenance, and Function

“…Along with the strong evidence that infectionor inflammation establishes Trm within NLT, there is also evidence that Trm develop within SLO (Marriott, Dutton, Tomura, & Withers, 2017; Schenkel, Fraser, & Masopust, 2014; Ugur, Schulz, Menon, Krueger, & Pabst, 2014). Utilizing parabiotic mice, Schenkel and colleagues demonstrated that a subset of viral-specific memory CD8 + T cells in SLO are in disequilibrium with the circulation and exhibit phenotypic signatures of tissue residency including CD69 expression (Schenkel etal.,2014).…”

“…This subpopulation of antigen-specific memory CD8 + T cells were enriched in IL-15-deficient mice, suggesting distinct mechanisms of persistence compared to circulating memory CD8 + T cells. In addition to the evidence that CD8 + Trm within SLO exist, two independent groups, utilizing in vivo cell labeling via photoconversion, have demonstrated that antigen-specific memory CD4 + T cells can establish residency within SLO (Marriott et al, 2017; Ugur et al, 2014). However, it remains unclear whether constitutive chemokine signaling regulates Trm maintenance within SLO.…”