1999;190:1123C1134

1999;190:1123C1134. are now recognized as the class of helper T cells that regulate the multiple stages of B cell immunity (Physique 1) [3C6]. After initial contact with antigen-experienced DC (Checkpoint I), antigen-specific effector TFH cells emerge as CXCR5+CCR7? TH cells that migrate to the follicular regions of lymphoid organs to form stable contacts with antigen-primed B cells (Checkpoint II). Subsequent to cognate B cell contact, a cohort of effector TFH cells migrate to germinal centers, form stable contacts with variant GC B cells (Checkpoint III) to regulate the development of antigen-specific memory B cell compartment in ways that remain poorly understood. Finally, memory TFH cells persist within the priming environment to regulate the antigen-specific memory B cell response to re-challenge (Checkpoint IV). We propose that the strength of antigen receptor binding, the duration of cellular contact and the molecular context of cognate interactions are the defining attributes of each developmental checkpoint in vivo. Open in a separate window Physique 1 COGNATE TH CELL REGULATION OF B CELL IMMUNITYFollowing local protein vaccination, mature antigen-experienced dendritic cells from the site of injection traffic to the draining lymphoid tissue to primary pMHCII-specific naive TH cells at Checkpoint Ia. Antigen can also be transported to the subcapsullar sinus by macrophage to Apoptozole present native cell associate antigen to B cells at Checkpoint Ib. Antigen-specific B cells will take up protein antigen, process and present pMHCII complexes and move towards T-B borders to interact with pMHCII-specific effector TFH cells at Checkpoint II. Following stable cognate contact a cohort of antigen-specific B cells will move into the follicular regions, massively expand to form secondary follicles, somatically diversify their BCR, express the variant BCR and then traverse FDC networks in the light zone of germinal center at continuous Checkpoint IIIa interactions. GC B cells expressing high affinity variant BCR form stable Apoptozole contacts with GC TFH cells at Checkpoint IIIb prior to GC exit and entry into the memory B cell compartment as either memory response precursors or long-lived plasma cells. Antigen-specific memory TFH cells and memory B cells persist in the priming lymphoid tissue to interact upon secondary challenge Apoptozole Rabbit Polyclonal to OR10Z1 with antigen at Checkpoint IV a requisite regulatory conversation for growth of memory B cells and formation of memory response plasma cells. INITIATING ADAPTIVE IMMUNITY: CHECKPOINT I Vaccines provide foreign antigen within an inflammatory context to initiate dendritic cell (DC) maturation. Antigen-experienced DC will express peptide-MHC class II (pMHCII) complexes and a spectrum of secreted and surface-expressed molecules to recruit naive pMHCII-specific TH cells (Checkpoint Ia), promote TH clonal growth and effector TH cell differentiation. The strength of TCR-pMHCII interactions and the extended molecular context of these cognate events impact antigen-specific TH cell fate and the acquisition of effector TH cell function. Our recent findings indicated the requirement of a threshold TCR affinity to reach maximal local clonal accumulation [7*]. Surprisingly, antigen dose did not alter the clonal selection threshold but changing the vaccine adjuvant altered clonal composition and pMHCII binding profiles of responder TH cells. More recently, we provided evidence for a casual link between TCR binding strength and the differentiation of effector TH cells [8**]. In this protein vaccination model, we recognized three separable sub-types of antigen-specific effector TH cells expressing a hierarchy of TCR binding strength. T-zone localized effector TH cells expressed the lowest binding, emigrant effector TH cells an intermediate binding and the effector TFH cell compartment the highest binding to pMHCII complexes. Hence, adjuvant controls the threshold for clonal selection and strength of TCR-pMHCII binding regulates the deployment of effector TH cell function. Naive B cells that can recognize soluble or cell-associated antigen with sufficient binding strength (Checkpoint 1b) will internalize antigen, process and present pMHCII complexes. Vaccine adjuvants can influence these early events in B cell priming through the engagement of innate receptors [9,10], however their mechanism of action and developmental result in vivo remains poorly resolved. Specific acknowledgement by BCR will lead to increased co-stimulatory molecule expression and movement towards T cell zones of secondary lymphoid tissue [11]. Here, the antigen-primed pMHCII-expressing B cells receive cognate help as a.