The initial engagement of the T cell receptor (TCR) through interaction with cognate peptide-MHC is a requisite for T cell activation and confers antigen specificity. While this is a key event in T cell activation, the duration of these interactions may affect the proliferative capacity and differentiation of the activated cells. Here, we developed a system to evaluate the temporal requirements for antigenic stimulation during an immune response, in vivo. Using antibodies that target specific antigens in the context of MHC, we were able to manipulate the duration of antigen availability to both CD4 and CD8 T cells during an active infection. During the primary immune response, the magnitude of the CD4 and CD8 T cell response was dependent on the duration of antigen availability. Both CD4 and CD8 T cells required sustained antigenic stimulation for maximal expansion. Memory cell differentiation was also dependent on the duration of antigen exposure, albeit to a lesser extent. However, memory development did not correlate with the magnitude of the primary response, suggesting that the requirements for continued expansion of T cells and memory differentiation are distinct. Finally, a shortened period of antigen exposure was sufficient to achieve optimal expansion of both CD4 and CD8 T cells during a recall response. It was also revealed that limiting exposure to antigen late during the response may enhance the CD4 T cell memory pool. Collectively, these data indicated that antigen remains a critical component of the T cell response after the initial APC-T cell interaction.

. Sex-specific behaviors of some vertebrates are reversible by androgen administered in adulthood. Such behavioral transformations in adulthood provide opportunities to identify how neural systems reconfigure to produce sex-specific behavior. In this study, we focused on the vocalizations of the African clawed frog, Xenopus laevis. Male and female adult Xenopus produce sexually distinct vocalizations; males produce series of rapid clicks, whereas females produce slow trains of clicks. The differences in click rate can be reduced to differences in the firing rate of laryngeal motoneurons in vivo. This behavioral dimorphism is accompanied by various sex-specific characteristics throughout the vocal pathways, including functionally distinct laryngeal muscles and motoneurons in the sexes. In this study, we first determined whether and how testosterone (T) modifies the vocalizations of adult females and then examined changes underlying the behavioral modification at the laryngeal muscle and motoneuron levels. Our results show that, in response to T, the vocalizations of females were transformed within 13 wk. Vocal transformation was preceded by complete masculinization of muscle contractile properties and motoneuron soma size by the fourth week of T treatment, which suggests that the vocal pathways' peripheral components masculinize earlier than the behavior. Therefore the rate of transformation of vocal behavior must reflect a functional transformation of neurons in the central vocal pathways, which leads to the generation of male-like motor rhythms.

b ␤2 (CD18) integrins with ␣-chains CD11a, -b, -c, and -d are important adhesion molecules necessary for leukocyte migration and cellular interactions. CD18 deficiency leads to recurrent bacterial infections and poor wound healing due to reduced migration of leukocytes to inflammatory sites. CD8 T cells also upregulate CD11a, CD11b, and CD11c upon activation. However, the role these molecules play for CD8 T cells in vivo is not known. To determine the function of individual ␤2 integrins, we examined CD8 T cell responses to Listeria monocytogenes infection in CD11a-, CD11b-, and CD11c-deficient mice. The absence of CD11b or CD11c had no effect on the generation of antigen-specific CD8 T cells. In contrast, the magnitude of the primary CD8 T cell response in CD11a-deficient mice was significantly reduced. Moreover, the response in CD11a ؊/؊ mice exhibited reduced differentiation of short-lived effector cells (KLRG1 hi CD127 lo ), although cytokine and granzyme B production levels were unaffected. Notably, CD11a deficiency resulted in greatly enhanced generation of CD62L؉ central memory cells. Surprisingly, CD8 T cells lacking CD11a mounted a robust secondary response to infection. Taken together, these findings demonstrated that CD11a expression contributes to expansion and differentiation of primary CD8 T cells but may be dispensable for secondary responses to infection.

The process of lymphopoiesis begins in the bone marrow (BM) and requires multiple cellular intermediates. For T cell production, lymphoid progenitors exit the BM and home to the thymus where maturation and selection ensues. These processes are dependent on a number of factors including chemokines and adhesion molecules. While the β2 integrin CD11a plays an important role in the migration of lymphocytes to lymph nodes, the role of CD11a in T cell development is largely undefined. Our studies now show that in CD11a−/− mice, thymic cellularity was decreased and early T cell development was partially impaired. Remarkably, CD11a was critical for generation of common lymphoid progenitors (CLPs) and lymphoid-primed multipotent progenitors (LMPPs). However, in intact CD11a−/− mice, peripheral B and T cell subsets were only modestly altered suggesting compensatory mechanisms were operating. In contrast, competitive BM reconstitution assays revealed an essential role for CD11a in the generation of thymocytes and mature T and B cells. This defect was linked to the requirement for CD11a in the development of CLPs. Furthermore, our results identified CLPs, and not LMPPs, as the requisite CD11a-dependent precursor for lymphocyte development. Thus, these findings established a key role for CD11a in lymphopoiesis.

Maturation of dendritic cells (DCs) regulates protein sorting in endosomal compartments to promote the surface expression of molecules involved in T cell activation. MHC Class II complexes are mobilized to the surface via intracellular effector molecules that remain largely unknown. We here show that protein kinase C (PKC) stimulates Class II antigen surface expression, using knock-in mice that express a Class II-green fluorescent protein fusion protein as a read out. Selective inhibition of PKCdelta counteracts the ability of DCs to stimulate Class II MHC-restricted antigen-specific T cells. Activation of PKC does not affect antigen uptake, peptide loading and surface display of Class I MHC and transferrin receptor in DCs. We show that activation-induced Class II MHC surface expression is dependent on activation of PKCdelta and conclude that this event is pivotal for optimal CD4 T cell activation.

In this article the author name Luigi Calligaris was incorrectly written as A. Calligaris. The original article has been corrected.

Deterministic rules, rather than experience, are thought to regulate the development of simple behaviors in vertebrates and invertebrates. We revisited this issue through examination of the sexually distinct vocalizations of African clawed frogs (Xenopus laevis), a reproductive behavior used by sexually mature males and females. We discovered that, as expected for simple behavior, female vocalizations develop through deterministic rules r. The rare calls of juvenile females are indistinguishable from those of adult females. The vocal pathways of juvenile females, as measured by the contractile properties of the laryngeal muscles (the vocal muscles) and the laryngeal motoneuron somata (vocal motoneurons) size, are the developmental default and do not differentiate as they mature. Male Xenopus, in contrast, produce extensive vocalizations with rudimentary acoustic structure before reaching sexual maturity. Moreover, the functional properties of the vocal central pattern generator mature before muscle fibers and motoneuron size are fully masculinized. The results suggest that neuronal activity during development may be important in organizing the contractile properties of the muscle fibers in male, but not in female Xenopus.

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