Type II membrane protein CD69 regulates the formation of resting T-helper memory

Abstract

Memory T-helper (Th) lymphocytes are crucial for the maintenance of acquired immunity to eliminate infectious pathogens. We have previously demonstrated that most memory Th lymphocytes reside and rest on stromal niches of the bone marrow (BM). Little is known, however, regarding the molecular basis for the generation and maintenance of BM memory Th lymphocytes. Here we show that CD69-deficient effector CD4 T lymphocytes fail to relocate into and persist in the BM and therefore to differentiate into memory cells. Consequently, CD69-deficient CD4 T cells fail to facilitate the production of high-affinity antibodies and the generation of BM long-lived plasma cells in the late phase of immune responses. Thus, CD69 is critical for the generation and maintenance of professional memory Th lymphocytes, which can efficiently help humoral immunity in the late phase. The deficit of immunological memory in CD69-deficient mice also highlights the essential role of BM for the establishment of Th memory.

Immunological memories of the bone marrow

“…Mice lacking CD103 show defects in establishing antigen‐experienced “tissue‐resident” T cells of peripheral tissues 162. For the establishment of bone marrow‐resident memory CD4 lymphocytes, we have shown that CD69 is essential 137. “Tissue‐resident” memory T cells have downregulated S1PR1, like CD69 + bone marrow memory T cells 33.…”

“…Expression of CD69 is induced upon activation of T cells138 and therefore has been conceived as a marker of activation, also for bone marrow memory T cells 133, 139. However, in murine bone marrow, neither CD69 + nor CD69 − memory CD4 + T cells are cycling according to Ki‐67 expression 137. In human bone marrow, both CD69 + and CD69 − memory T cells have transcriptomes of quiescent cells, with very few genes differentially expressed between them.…”

“…Aside from its role in retaining memory T lymphocytes in the bone marrow, CD69 is essential for getting them into the bone marrow in the first place 137. CD69‐deficient CD4 + T cells, while mounting immune reactions comparable to their wildtype counterparts, failed to establish a population of bone marrow‐resident memory T cells.…”

“…This observation also suggests that the lifestyle of resident memory T cells of the bone marrow might be not so different from the lifestyle of memory plasma cells. In murine bone marrow, memory CD4 + and CD8 + T lymphocytes are found in close association if not direct contact with stromal cells 59, 117, 137, 145. They are individually dispersed throughout the parenchyme 117.…”

Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma

“…Through CD69 targeting and deficiency experiments, Alari-Pahissa et al (2012) revealed that CD69 might have multiple immunoregulatory roles. CD69 has also been thought to play important roles in the generation and maintenance of professional memory Th lymphocytes (Shinoda et al, 2012). CD69 + T cells were demonstrated to induce indoleamine 2,3-dioxygenase in tumor-associated macrophages and hence to down-regulate inflammatory immune responses (Zhao et al, 2012).…”