Recirculating CD4 memory T cells mount rapid secondary responses without major contributions from follicular CD4 effectors and B cells

Abstract

For weeks after primary immunization with thymus-dependent antigens the responding lymph nodes contain effector CD4 T cells in T zones and germinal centers as well as recirculating memory T cells. Conversely, remote nodes, not exposed to antigen, only receive recirculating memory cells. We assessed whether lymph nodes with follicular effector CD4 T cells in addition to recirculating memory CD4 T cells mount a more rapid secondary response than nodes that only contain recirculating memory cells. Also, the extent to which T cell frequency governs accelerated CD4 T cell recall responses was tested. For this, secondary antibody responses to a superantigen, where the frequency of responding T cells is not increased at the time of challenge, were compared with those to conventional protein antigens. With both types of antigens similar accelerated responses were elicited in the node draining the site of primary immunization and in the contralateral node, not previously exposed to antigen. Thus recirculating memory cells are fully capable of mounting accelerated secondary responses, without the assistance of CD4 effector T cells, and accelerated memory responses are not solely dependent on higher T cell frequencies. Accelerated memory CD4 T cell responses were also seen in B cell-deficient mice. IntroductionPrimary immunization with thymus-dependent antigens results in specific T and B cell responses in draining lymph nodes (LN). Naive CD4 T cells enter cell cycle after being primed by cognate interaction with dendritic cells in the T zones. This results in a strong expansion of antigen-specific lymphocytes within the LN [1]. The high number of antigen-responding CD4 T cells typically is not sustained, and only a small proportion of the cells persists [2,3]. Nevertheless, CD4 memory T cells can survive for long periods without continued contact with antigen [4][5][6], although it has been reported that such antigen-deprived cells may lack competence on reactivation in vivo [7].Antigen-experienced CD4 T cells have been classified into central memory and effector memory cells [8]. Central memory T cells have a slow turnover and express high levels of CCR7 and CD62L, which are both associated with homing to T zones of lymphoid tissues. Conversely, effector memory T cells home to inflamed tissues, have a rapid turnover, and are CCR7 -CD62L low . Both effector and central memory populations in vitro respond rapidly to low doses of antigen, but while LN draining the site of immunization develop substantial populations of antigen-specific CD4 effector T cells located in the follicles and outer T zone; these are not found in the remote LN. After immunization with limiting amounts of antigen, most antigen is trapped in the LN draining the site of immunization (draining LN) and lymphocyte activation is limited to this site. Several weeks after immunization draining LN will contain effector and memory CD4 T cells. In contrast, LN remote from the site of primary immunization (remote LN) will only have received recirculating memory ...

Systemic Flagellin Immunization Stimulates Mucosal CD103+ Dendritic Cells and Drives Foxp3+ Regulatory T Cell and IgA Responses in the Mesenteric Lymph Node

“…Molecules of a similar size are able to disperse rapidly throughout the host and prime in multiple sites (43), and this explains why T cell activation and proliferation was synchronous after sFliC. In contrast, alum-precipitated proteins given s.c. tend to prime in draining LN, but not necessarily in other sites (44)(45)(46).…”

Early simultaneous production of intranodal CD4 Th2 effectors and recirculating rapidly responding central‐memory‐like CD4 T cells

“…It promotes Th2 responses with the induction of Th2 cytokines in CD4 T cells [16] and strong antibody production associated with elevated titers of the Th2-dependent IgG1 and IgE antibodies [17]. We previously reported that several weeks after immunization with alumprecipitated Ag recirculating memory CD4 T cells are found in lymphoid organs not exposed to the Ag and mount accelerated secondary responses [18]. In the present study we questioned the precise timing of appearance and responsiveness of recirculating memory CD4 T cells in Ag-free lymphoid organs.…”

“…Importantly, these early central-memory-like cells are immediately responsive to further Ag stimulation and produce effectors more rapidly than naïve cells. In addition to early memory formation there is production of effector helpers that produce Th2 cytokines [16] and direct B cells to undergo Ig class switching and to form plasmablasts and germinal centers [17][18][19]. Finally, the effect of the initial T-cell precursor frequency has been considered, for evidence has emerged that this can influence central and effector memory commitment [20], and memory T-cell survival [21,22].…”

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

“…This approach would allow us to identify when populations were generated and clarify the movement of memory CD4 + T cells to other secondary lymphoid tissue or their retention in the draining LN. Immunisation of the murine paw pad has been used to target a specific peripheral LN, often the popliteal LN . We immunised the front paw pad to target the brachial LN (bLN) given its greater size and the scarcity of endogenous CD4 + T cells responsive to a given peptide .…”