CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs

Abstract

Naive lymphocytes continually enter and exit lymphoid organs in a recirculation process that is essential for immune surveillance. During immune responses, the egress process can be shut down transiently. When this occurs locally it increases lymphocyte numbers in the responding lymphoid organ; when it occurs systemically it can lead to immunosuppression as a result of the depletion of recirculating lymphocytes. Several mediators of the innate immune system are known to cause shutdown, including interferon alpha/beta (IFN-alpha/beta) and tumour necrosis factor, but the mechanism has been unclear. Here we show that treatment with the IFN-alpha/beta inducer polyinosine polycytidylic acid (hereafter 'poly(I:C)') inhibited egress by a mechanism that was partly lymphocyte-intrinsic. The transmembrane C-type lectin CD69 was rapidly induced and CD69-/- cells were poorly retained in lymphoid tissues after treatment with poly(I:C) or infection with lymphocytic choriomeningitis virus. Lymphocyte egress requires sphingosine 1-phosphate receptor-1 (S1P1), and IFN-alpha/beta was found to inhibit lymphocyte responsiveness to S1P. By contrast, CD69-/- cells retained S1P1 function after exposure to IFN-alpha/beta. In coexpression experiments, CD69 inhibited S1P1 chemotactic function and led to downmodulation of S1P1. In a reporter assay, S1P1 crosslinking led to co-crosslinking and activation of a CD69-CD3zeta chimaera. CD69 co-immunoprecipitated with S1P1 but not the related receptor, S1P3. These observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-alpha/beta, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.

Enhanced trafficking to the pancreatic lymph nodes and auto-antigen presentation capacity distinguishes peritoneal B lymphocytes in non-obese diabetic mice

“…4d). Shiow and colleagues [17] have demonstrated that high levels of CD69 downregulate S1P receptor 1 surface expression without substantially affecting S1P receptor mRNA expression. As seen in Fig.…”

“…However, when the surface expression of S1P receptor 1 was examined, it was found to be lower on NOD than on BALB/c peritoneal B cells. This could be explained by a cross-communication between CD69 and S1P receptor 1 [17]. High levels of CD69 downregulate S1P receptor 1 surface expression specifically, without substantially affecting S1P receptor mRNA expression.…”

“…High levels of CD69 downregulate S1P receptor 1 surface expression specifically, without substantially affecting S1P receptor mRNA expression. Moreover, high levels of CD69 functionally inhibit S1P receptor 1, causing cells to lose their chemotactic response to S1P [17]. The cross-communication between S1P receptor 1 and CD69 appears to be reciprocal, since stimulation with S1P downregulates CD69 on NOD T cells [20].…”

“…Antigen presentation assay NOD and BALB/c mice were immunised subcutaneously on the hind flank with 50 μg insulin peptide (Insulin B [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]; Anaspec, San Jose, CA, USA). After 10 days, spleens were collected from these animals and splenic CD4 + T cells purified using CD4 MicroBeads (Miltenyi Biotec, Bergisch Gladbach, Germany).…”

Immunological memories of the bone marrow

“…CD69 is an antagonist of S1PR1, blocking the S1P‐mediated egress of lymphocytes from secondary lymphoid organs into the blood 140, 141, 142. It is remarkable that in CD69 + memory T cells of bone marrow, S1PR1 expression is blocked on the level of transcription, since it has also been reported that CD69 can directly block surface expression of S1PR1 143.…”