Unique Ability of Activated CD4+ T Cells but Not Rested Effectors to Migrate to Non-lymphoid Sites in the Absence of Inflammation

Abstract

Recent studies suggest that effector T cells generated by immune responses migrate to multiple non-lymphoid sites, even those without apparent expression of antigen or inflammation. To investigate the ability of distinct CD4؉ T lymphocyte subsets to enter and persist in non-lymphoid, noninflamed compartments, we examined the migration and persistence of naïve, effector, and rested effector CD4؉ T cells generated in vitro following transfer to nonimmunized adoptive hosts. Th1 and Th2 effectors migrated to both lymphoid and non-lymphoid organs (peritoneum, fat pads, and lung). In contrast, rested effectors and naïve cells migrated only to lymphoid areas. Adhesion molecule expression, but not chemokine receptor expression, correlated with the ability to enter non-lymphoid sites. Donor cells persisted longer in lymphoid than in non-lymphoid sites. When hosts with naïve and memory donor cells were challenged with antigen, effectors developed in situ, which also migrated to non-lymphoid sites. Memory cells showed an accelerated shift to non-lymphoid migration, in keeping with memory effector formation. These results suggest that only recently activated effector T cells can disperse to non-lymphoid sites in the absence of antigen and inflammation, and as effectors return to rest, they lose this ability. These data also argue that memory cells in lymphoid sites are longer lived and not in equilibrium with those in non-lymphoid sites.

The effector to memory transition of CD4 T cells

“…We have previously shown that only the most activated and differentiated donor CD4 T cells migrate to the lung during the peak of the primary flu infection [70]. This cohort of responding cells also resembles 4-day in vitro generated Th1-polarized effectors, both in terms of phenotype and cytokine production (IFNc high , IL-2 low ), and we have also shown that only highly activated in vitro-generated effectors migrate to the lung [71]. After viral clearance, about day 9-10 post-infection, numbers of donor cells in the lung fall dramatically (Fig.…”

“…For example, memory CD4 T cells may influence various APC, B cells, and CD8 T cells via the rapid production of large amounts of Th1-or Th2-polarized cytokines as well as IL-2. However, other important properties, such as migration to non-lymphoid tissues, are only evident after memory cells re-expand into highly activated cells (memory or secondary effectors) [71]. Thus, re-activated memory CD4 T cells can also impact later phases of protective responses with similar kinetics as primary effectors arising from naïve precursors.…”

Coadministration of Interleukins 7 and 15 with Bacille Calmette‐Guérin Mounts Enduring T Cell Memory Response againstMycobacterium tuberculosis

“…Even though the adaptive immune response is initiated in the local lymph nodes and thereafter effectors migrate to the site of infection [33][34][35][36], it is important to establish this proposition in the present study as well, because immunity of the lungs plays a seminal role in imparting protection against M. tuberculosis. Consequently, we next studied the status of T cell memory in the lungs.…”

“…33 (Figures 1A-1C). Furthermore, compared with those isolated from the BCG groups, lymphocytes isolated from mice in the BCG7.15 groups showed significantly higher production levels of IFN-g ( ) ( Figure 1D).…”

Analysis of naïve lung CD4 T cells provides evidence of functional lung to lymph node migration

“…Discussion Naïve CD4 T cells generally have been considered to reside principally within the secondary lymphoid organs, including the lymph nodes and spleen, and to be largely excluded from nonlymphoid tissues (8), although some reports have indicated that CD4 and CD8 T cells with a naïve phenotype can be found in such tissues (10,41). In contrast, memory and effector cells can gain access to nonlymphoid organs, where they can provoke immediate responses when confronted with their cognate antigens under appropriate conditions (42)(43)(44). In the present study, we found that the majority of CD4 T cells extracted from the lungs had a naïve phenotype.…”